Ion-selective electrodes based on molecular tweezer-type neutral carriers

Talanta 63 (2004) 61–71

Review

Ion-selective electrodes based on molecular tweezer-type neutral carriers Jun Ho Shim a , In Seok Jeong a , Min Hyung Lee a , Hun Pyo Hong a , Jeung Hoon On a , Ki Soo Kim b , Hong-Seok Kim b , Byeong Hyo Kim a , Geun Sig Cha a , Hakhyun Nam a,∗ a

Chemical Sensor Research Group, Department of Chemistry, Kwangwoon University, Seoul 139-701, Republic of Korea b Department of Industrial Chemistry, Kyungpook National University, Taegu 702-701, Republic of Korea Received 28 October 2003; received in revised form 17 December 2003; accepted 18 December 2003

Abstract Potentiometric properties of cholic and deoxycholic acid derivatives substituted with various ion-recognizing moieties, such as dithiocarbamate, bipyridyl, glycolic and malonic diamides, urea and thiourea, and trifluoroacetophenons (TFAP), have been studied using solvent polymeric membranes. The dithiocarbamate and bipyridyl group containing ionophores exhibit high silver ion selectivity. The cholic acid derivatized with glycolic diamides exhibited high calcium selectivity, but its complex formulation constant was 105 times smaller than that of ETH 1001. The reduced calcium binding ability of the glycolic diamide-substituted ionophore was advantageous for eliminating anionic interference. The bi- or tripodal malonic diamide-substituted ionophores exhibited substantially increased magnesium selectivity. Anion-selective ionophores have been designed by substituting urea and thiourea group containing chains to the hydroxyl linkers of chenodeoxycholic acid frames; their selectivity closely followed the sequence of Hoffmeister series, except the unusually large response of the thiourea-substituted ionophore to sulfate. The most successful examples of cholic or deoxycholic acid frame-based ionophores are those functionalized with two carbonate-selective TFAP groups: bipodal TFAP groups behaves like a tweezers for the incoming carbonate, and exhibit analytically interference free and quantitative responses to the carbonate in serum and seawater samples. © 2004 Elsevier B.V. All rights reserved. Keywords: TFAP; Ionophore; Tweezer

1. Introduction Ion-selective electrodes (ISEs) are a typical example of chemical sensors that use the principle of molecular recognition chemistry. They are readily prepared by immobilizing host molecules capable of recognizing a specific class of guest ionic species in an appropriate polymeric matrix system, which are then mounted on electrode body composed of Ag/AgCl wire and internal filling solutions. In the last three decades, because of their easy preparation and simplicity in use, ISEs have been not only practical solutions to a great variety of analytical problems but also useful tools for probing host–guest chemistry. Numerous researchers have shown that the analytical performance of ISEs depend most critically on the quality of host ionophore incorporated in the solvent polymeric membranes, even though the type and relative compositions ∗

Corresponding author. Tel.: +82-2-940-5246; fax: +82-2-911-8584. E-mail address: [email protected] (H. Nam).

0039-9140/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.talanta.2003.12.050

of all other components used to construct the membrane greatly vary their electroanalytical properties [1,2]. For this reason, design and synthesis of new ionophores have always attracted great interests [3]. Some examples of recent research activities in ionophores include the new crown ethers containing bulky subunits or thiazoles [4–8], anion-selective compounds having hydrogen-bonding functional groups (e.g., urea, thiourea and guanidine) on rigid molecular frames [9–13], and calixarens with ion-recognizing pendants at the lower or upper rims [14–17]. However, it is rare to find new ionophores that provide substantially enhanced potentiometric performance compared to the ones commercially available or known in the literature. In addition, further research efforts are called for to develop ionophores that is selective to transition metal ions other than silver, and to certain anionic species overruling the limitation imposed by Hoffmeister series. We have been engaged in the design and synthesis of new ionophores in the last several years, finding that the substitution of ion-recognizing moieties on the rigid cholic,

62

J.H. Shim et al. / Talanta 63 (2004) 61–71

efforts on the potentiometric characterization of such cholic or deoxycholic acid derivative-based ionophores including those not published in our previous reports.

2. Experimental 2.1. Preparation of ionophores and potentiometric evaluation Deoxycholic and cholic acid-based ionophores have been synthesized from the commercially available precursors: deoxycholic acid a1 has two parallel –OH groups on C3 and C12 positions, and cholic acid a2 three –OH groups on C3, C7 and C12. First, highly lipophilic deoxycholic and cholic amide molecular frames, b1 and b2, were synthesized by substituting dioctylamine to the corresponding carboxylic acids, a1 and a2, as shown in Scheme 1. To substitute ion-recognizing moieties on the rigid deoxycholic and cholic amide scaffold, the hydroxyl groups of b1 and b2 were changed to chloroacetyl groups, yielding, respectively c1 and c2. Other frame molecules were synthesized by substituting azides to the chloroacetyls of c1 and c2, followed by reducing them to amines to yield corresponding d1 and d2. The synthetic details of preparing deoxycholic and cholic amide scaffolds c1, c2, d1 and d2 may be found in the references [19,20], in the supplementary information of the reference [24]. Ionophores shown in Fig. 2 were synthesized as described in Scheme 2, starting from the molecular scaffolds of Scheme 1, Ionophore 1 was synthesized by refluxing the mixture of c1 and N,N-diisobutyldithiocarbamate dissolved in THF for 24 h. Ionophore 2 was synthesized from b1 by substituting bipyridines in basic condition [25]. Ionophores 3–6 were synthesized from d1 and d2 using corresponding acids with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole hydrate (HOBT) [24]. Ionophores 10–14 were synthesized from the frames b1 and b2 by substituting TFABs to the hydroxyl groups in basic conditions [19–21]. Ionophore 7 and 8 were synthesized with the different steroid frames, chenodeoxycholic acid derivatives with aminopropyl ether linkers, by reacting with phenyl isocyanate (and phenyl thioisocyanate) in dry chloroform.

Fig. 1. Molecular tweezers based on steroidal frame.

deoxycholic and chenodeoxycholic acid derivative frame results in tweezer-type ionophores [18–25]. Cholic acid has three hydroxyl linkers at C3, C7 and C12 carbons, which are lined in the same direction, approximately parallel and about 4.6–6.1 Å apart each other on the conformationally rigid steroidal ring structure [18]. Deoxycholic acid (which has two hydroxyl linkers at C3 and C12) and chenodeoxycholic acid (which has hydroxyl linkers at C3 and C7) also provide rigid molecular frame. Substituting molecule-recognizing groups, e.g., amides, urea, thiourea, thiophenes, bipyridines, dithiocarbamates and trifluoroacetophenones (TFAP), to those hydroxyl groups, it is possible to synthesize various kinds of molecular tweezers based on rigid cholic acid platform as shown in Fig. 1. For example, we have already shown that the cholic acid derivatives substituted with two or three TFAP units may serve as a highly selective molecular tweezers for the carbonate ion, and it is possible to determine carbon dioxide even in seawater which contains high concentration of anionic interferents like chloride (∼0.6 M) [21–23]. Encouraged by the result of tweezer-type carbonate ionophores, we attempted to synthesize new cholic acid frame-based ionophores that are highly selective to calcium, silver and anions. In this article, we summarize our recent Me H

Me

OH

Me COOH

OR

X OH

Me H

Me

Me CON(C8H17)2

X’ OR

a1; X = H a2; X = OH

b1; R = H, X’ = H, b2; R = H, X’ = OR O Cl c1; R = , X’ = H, c2 ; R = O NH2 d1; R = , X’ = H, d2 ; R =

Scheme 1. Synthesis of deoxycholic and cholic amide scaffolds.

O Cl

, X’ = OR

O NH2

, X’ = OR

J.H. Shim et al. / Talanta 63 (2004) 61–71 Me H Me

Me

Me H

Me CON(C8H17)2

O

63 Me

CON(C8H17)2

O

O

O O

O S

O

O

S

N N

S S

N

N

N

N

2

1 Me H

Me

O

Me Me H

Me

CON(C8H17)2

O

Me

X O

O

X

O O

HN

O

NH O

O

O

CON(C8H17)2

O

O

NH

HN

O

O

O

O

O

H15C7

H15C7

O Me

Me

N

N Me Me

N

N C7H15

C7H15

3; X = H 4; X = OCOCH2NHCOCH2OCH2CON(Me)C7H15

5; X = H 6; X = OCOCH2NHCOCH2CON(Me)C7H15

Me Me

Me

Me

Me Me

O

O

O Si

O

O

O

O

O

O

Si

HN

Si

O

NH

HN

HN

O

NH HN

O

HN

S

NH

NH

S

NH

HN

O

NH

7

8

Me H

Me

9

Me

Me H

Me CON(C8H17)2

OR3 OR2

Me

CON(C8H17)2

O O

OR1

O O

10; R1 = R2 = TFAB, R3 = Ac 2

3

F

F3C

F

1

11; R = R = TFAB, R = Ac F

F

O

O

CF3

14

12; R1 = R3 = TFAB, R2 = Ac

F

13; R1 = R2 = R3 = TFAB

F

F

F

F

CF3

TFAB = O O

Fig. 2. Deoxycholic and cholic acid derivative-based ionophores discussed in this work.

64

J.H. Shim et al. / Talanta 63 (2004) 61–71 Me H

Me

Me CON(C8H17)2

OR

Me CON(C8H17)2

OR’

X

X’

OR

OR’

b1; R = H, X = H, b2; R = H, X = OR O Cl c1; R = ,X=H O Cl c2; R = , X = OR O NH2 d1; R = ,X=H O d2; R =

Me H

Me

NH2

O

O S

1; R’ =

N

, X’ = H

5; R’ =

O

S O O

N

N

2; R’ =

, X’ = H O

3; R’ =

H N

, X = OR

O O

O 4; R’ =

H N

6; R’ =

O Me N C7H15 , X’ = OR’

H N O

Me N C7H15, X’ = H

12; R’ = TFAB, X’ = OAc

Me N C7H15, X’ = OR’

14; R’ = TFAB, X’ = H

O

13; R’ = TFAB, X’ = OR’

O

O O

Me N C7H15 , X’ = H

H N

O

O TFAB =

O CF3

Scheme 2. Synthesis of deoxycholic and cholic acid-based ionophores from the molecular scaffolds shown in Scheme 1.

Potentiometric evaluation of the ionophores 1–14 shown in Fig. 2 was carried out in usual manner as described in our previous articles [19–25]. Solvent polymeric membranes were prepared by adding 1–2 wt.% of selected neutral carrier into the matrix composed of 1:2 ratios of PVC [or mixture of PVC and polyurethane (PU)] and plasticizer [2-nitrophenyl octyl ether (NPOE), dioctyl adipate (DOA), or dioctyl sebacate (DOS)]. To enhance the catalytic ion transfer between the organic membrane and aqueous sample, cationic [tridodecylmethylammonium chloride (TDMACl)] or anionic [potassium tetrakis(p-cholorophenyl)borate (KTpClPB)] lipophilic additives was also added to the membrane cocktail in 0–100 mol% relative to the neutral carrier. If necessary, the amount of a neutral carrier and the corresponding lipophilic additive added to the membrane were varied to obtain optimal potentiometric response (for example, about 4 wt.% in case of TFAP derivatives). Membrane cocktails dissolved in THF were cast on a slide glass, dried for a day, cut with a borer, and mounted on an electrode body (IS-561, Glasbläserei MÖller, Zürich, Switzerland). Appropriate internal reference solutions containing primary target ions were filled to assemble ISEs. Electrodes were, then, presoaked for 0–24 h in buffer or distilled water or solutions containing the primary ions of interest before use. Most experiments were carried out in appropriate concentration (0.01–0.1 M) of Tris–HCl, Tris–H2 SO4 , or HEPES–NaOH buffer solutions at near neutral pH (7.0–7.4), except for the test of carbonate-selective membranes (alkaline conditions: pH 8.6). On the other hand, we used an acidic magnesium acetate buffer (0.01 M, pH 4.5) to test transition metal ions. The potential differences between the ISEs and the reference electrode (Orion sleeve-type double junction Ag/AgCl reference electrode; model 90-02) were measured using a PC equipped with high-impedance input 16-channel analog-to-digital converter (KOSENTECH, Busan, Korea). Dynamic response curves and calibration plots were ob-

tained through the step addition of standard solutions to 200 ml of background buffer electrolyte at room temperature. The solutions were magnetically stirred during the recording of all emf values. Selectivity coefficients were determined by using the matched potential method [26–28]. The detection limits of the electrodes were obtained from the calibration curves, as described elsewhere [27,28]. In this article, we expressed the results in molarity unit for monovalent ions without considering their activity, while divalent ions with activity coefficients.

3. Results and discussion 3.1. Cation-selective ionophores In this research, we first attempted to design new cation-selective ionophores that would exhibit enhanced potentiometric performance for transition metal ions. While there are some transition metal ion-selective neutral carriers available from the literature and also from commercial products, it has been our experience that the ISEs based on those ionophores often result in poorly reproducible or irreversible responses, a typical phenomena observed when the neutral carrier and guest ion form too a tight complex. Since the transition metal ion-recognizing moieties may be substituted in parallel to the hydroxyl linkers on C3 and C12 positions of the rigid cholic acid or deoxycholic acid derivatives, and they may have limited freedom in binding the incoming ions, we presumed that the newly synthesized tweezer-type neutral carriers may form less tight complex with the guest ions. It may provide improved reversibility and reproducibility with less poisoning effect. Extending the idea of tweezer-type cation-selective ionophore, we then prepared calcium- and magnesium-selective neutral carriers that exhibit drastically reduced anionic interfering responses.

J.H. Shim et al. / Talanta 63 (2004) 61–71

65

Table 1 Potentiometric characteristics of silver ion-selective electrodes based on ionophore 1 and 2 Ionophore

54.9 50.4 b c

−8.9 −6.4

pot

Selectivity coefficient (log kAg+ ,j ) Cd2+

Ni2+

Fe2+

Co2+

Pb2+

Zn2+

Cu2+

<−7.8 <−5.0

<−7.8 <−5.0

<−7.8 <−5.0

<−7.8 <−5.0

<−7.8 <−5.0

<−7.8 −4.9

<−7.5 −0.3

Slopes from 10−7 to 10−3 M (mV per decade). Slopes from 10−6 to 10−3 M. log [Ag+ ].

3.1.1. Transition metal ion-selective ionophores Many transition metal ion-selective ionophores have binding site formed with sulfur or nitrogen containing groups. For our first attempt, we selected dithiocarbamate and bipyridyl groups as the possible cation-selective moieties [29]. Ionophores 1 and 2 in Fig. 2 show the structure of the ionophores. Preparing the membranes composed of 1 wt.% of 1 or 2, 33 wt.% PVC, and 66 wt.% plasticizer dioctyl adipate (DOA), we measured their responses to various cationic species. The dependence of detection limits on the composition of internal filling solutions proposed by Pretsch and co-workers was also examined with these new ionophores [30]. It was observed that the ISEs based on ionophore 1 exhibit high selectivity to silver ion, and the results are summarized in Table 1. It was noted that the ionophore 1-based electrode has low detection limit similar to that based on the ionophore o,o -bis[2-(methylthio)ethyl]-tert-butylcalix[4]arene, and exhibited super Nernstian response in the 10−9 to 10−7 M range as observed by Bakker and co-workers [31]. ISEs that exhibit super Nernstian response to transition metal ions often lack potentiometric reproducibility, and rarely return to their background potential once they were tested with selective ions. We, thus, examined the potentiometric reproducibility of the ionophore 1-based electrode by repeating the potentiometric titration from 10−9 to 10−3 M several times. Fig. 3 shows the results: the background potentials have increased substantially after the first test, and gradually until fourth test to a level of 10−6 M of silver ion. The reproducibility over 10−6 M [Ag+ ] was excellent, and the background potential was partially recovered when the electrode was washed with high concentration of sodium chloride. The detection limit of the ionophore 1-based electrode to silver ion was substantially lowered to 100 ppt (10−9 M) when the internal filling solution composed of 10−3 M AgNO3 /10−3 M NaNO3 /5 × 10−2 M EDTA, which effectively reduces the concentration of Ag+ in inner solution below 10−9 , was used (see Fig. 4) [30]. A full report on ionophore 1 and its related derivatives will be published elsewhere. These results certainly demonstrate that the cholic acid derivative with dithiocarbamate is superior to other silver ion-selective ionophores based on calix[4]arenes [15–17]. The electrode based on ionophore 2, bipyridyl substituted cholic acid derivative, also exhibited high selectivity

400 -3

10 M

300

-4

10 M -5

EMF / mV

a

Detection limitc

10 M -6

-7

10 M

10 M

200

1st 2nd 3rd 4th

100

0 0

200

400 600 Time, sec

800

1000

Fig. 3. Reproducibility of the ionophore 1-based silver ion-selective electrode: four consecutive runs of dynamic responses to silver ion were recorded from 10−7 to 10−3 M in magnesium acetate buffer (10−2 M, pH 4.5).

to silver ion, but suffered from high interfering response to copper ion. The electrode exhibited slow response to copper ion with super Nernstian slope, and lost its sensitivity after the copper ion test, indicating that the copper ion is

50 mV EMF / mV

1a 2b

Slope

-10

-9

-8

-7 -6 -5 + Log [Ag , M]

-4

-3

Fig. 4. Calibration plots of the ionophore 1-based electrodes with different inner filling solutions: 10−3 M AgNO3 /10−3 M NaNO3 /5 × 10−3 M Na2 EDTA (); 10−3 M AgNO3 /10−3 M NaNO3 /10−2 M Na2 EDTA (䊐); 10−3 M AgNO3 /10−3 M NaNO3 /10−1 M Na2 EDTA (䊊); 10−3 M AgNO3 /10−3 M NaNO3 /5 × 10−2 M Na2 EDTA (䊉).

J.H. Shim et al. / Talanta 63 (2004) 61–71

strongly complexed between the bipyridyl groups. We have synthesized various types of cholic and deoxycholic acid derivatives substituted with dithocarbamates and bipyridyls attached to electron donating or withdrawing groups, and investigated if such modifications around the biding site yield the transition metal ion-selective neutral carriers with improved analytical performance. Experimental results on this subject will be published elsewhere. 3.1.2. Calcium-selective ionophores Calcium ion, one of the most important electrolyte in physiological systems, is known to form 1:2 and 1:3 complexes with the non-cyclic diamides, e.g., (−)-(R,R)-N,N (bis(11-ethoxycarbonyl)undecyl)-N,N -4,5-tetramethyl-3,6dioxaoctanediamide (ETH 1001) and N,N,N ,N -tetracyclo3-oxapentanediamide (ETH 129), respectively [32]. Both ETH compounds have been most widely used in the construction of calcium-selective electrodes, clinical analyzers, and in the model study of calcium transport phenomena in biological systems. The calcium-selective electrodes based on these ionophores, however, exhibit large interfering responses to lipophilic anions (e.g., ClO4 − , SCN− , I− , Br− and salicylate), e.g., they result in anionic response or considerably decreased sensitivity in the presence of such anions. If the ionophore has high cation selectivity with a large complex formation constant, the ionophore–cation complex formed in the membrane may act like cationic sites, causing a large anionic interference. Thus, it was assumed that the use of an ionophore with reduced cation binding constant may decrease the anionic interference problem. Molecular modeling study showed that the compounds with two or three glycolic diamides linked to deoxycholic or cholic acid (ionophore 3 and 4) can capture the calcium ion within the binding cavity formed by six and nine oxygen atoms (Ca2+ -oxygen distance: 233–276 pm), respectively, resulting in a 1:1 complex without undergoing large conformational changes. However, the glycolic diamides are fixed on the rigid frame and may not be able to assume an optimal conformation in binding calcium ion, resulting in the less tight complex. To test such hypothesis, potentiometric evaluations have been made with the membrane comprising PVC (32.9 wt.%), NPOE (65.9 wt.%), 50 mol% KTpClPB, and ionophore 3 or 4 (1.0 wt.%). As summarized in Table 2, the potentiometric performance of ionophore 3-based electrode is nearly the same as Table 2 Potentiometric characteristics of calcium ion-selective electrodes based on ionophore 3 and 4 Ionophore

3 4

Slopea

31.7 30.1 a b

3.1.3. Magnesium-selective ionophores We examined if the ISEs based on the ionophore 5 and 6, which have two and three pendant malonic diamide chains on the rigid cholic acid frame, would exhibit selective

100 Ionophore 3

50

0 ETH 1001

-50

-100

pot ) Ca2+ ,j

Detection limitb

Selectivity coefficient (log k Mg2+

Li+

Na+

K+

NH4

−6.6 −6.4

−4.2 −4.0

−4.2 −4.1

−4.6 −4.4

−4.8 −4.7

−4.2 −4.2

Slopes from 10−5 to 10−1 M (mV per decade). log [Ca2+ ].

that of ETH 1001- or ETH 129-based electrodes, providing Nernstian response in the 10−5 –10−1 M range, and a low detection limit (2.5 × 10−7 M). However, the calcium selectivities of the 3-based electrode over Na+ , K+ and NH4 + are 5–7 times inferior to those of the ETH ionophore-based electrodes, indicating that the calcium binding ability of ionophore 3 is weaker than that of ETH 1001 or ETH 129. The potentiometric responses of the ionophore 4-based electrode were similar to those of the ionophore 3-based electrode, suggesting that the calcium binding by two and three pendant glycolic diamides is not much different. Potentiometric complex formation constants of calciumselective neutral carriers (ETH 1001, ETH 129, and ionophore 3) have been determined using the method proposed by Bakker et al. [33]; the formation constant of ionophore 3 in the solvent polymeric membrane was about 106 times smaller than ETH 1001 and ETH 129 [24]. The moderate calcium binding ability of ionophore 3 may be advantageous for reducing the anionic interference problem. The effect of anionic interference is further demonstrated in Fig. 5, using Ca(SCN)2 : the response of ETH ionophore-based electrodes turned into anionic one in the 10−3 –10−2 M range, while that of the 3-based electrode is linear up to 10−1 M. The ETH 1001 and ETH 129-based electrodes exhibited curved or leveled off responses over 10−4 M when the measurements were made in the presence of 0.01 M of lipophilic anions, e.g., perchlorate, iodide, and salicylate, while the response of the ionophore 3-based electrode were not affected. These results support that certain potentiometric properties of ISEs could be modified using rationally designed ionophores.

EMF / mV

66

ETH 129 +

-6

-5

-4 -3 2+ log[Ca , M]

-2

-1

0

Fig. 5. Calibration plots of the ionophore 3-based electrode to the step addition of Ca(SCN)2 from 10−6 to 10−1 M. Background electrolyte: 10−2 M Tris–HCl, pH 7.4.

J.H. Shim et al. / Talanta 63 (2004) 61–71

response to magnesium [41]. The importance of magnesium ion in clinical chemistry has been discussed [34], and the design of magnesium ion-selective neutral carriers with improved analytical performance has attracted great attention [35–38]. Several well known magnesium ion-selective neutral carriers contain two or three malonic diamide chains attached to phenyl ring, alkyl chain, nitrogen, or azacrown ethers; although their magnesium selectivities over calcium ion need further improvement, they are now being used in clinical analysis [39]. We attempted to introduce two or three malonic diamides to rigid cholic acid frame, and examined the change in their potentiometric properties using the membranes composed of PVC (32.5 wt.%), NPOE (66.0 wt.%), KTpClPB (50 mol%), and neutral carrier 5 or 6 (1.0 wt.%). As shown in Fig. 6 and summarized in Table 3, the electrodes based on ionophore 5 and 6 exhibited substantially increased magnesium ion selectivity over calcium ion. Interestingly, the ISE based on ionophore 6, which has three malonic diamides, resulted in higher magnesium ion selectivity than that based on ionophore 5. The magnesium ion selectivity of the ionophore 5- and 6-based electrodes is Ionophore 5

140

2+

Mg

120

Ca

2+

+

K

EMF / mV

100

Na

+

80 60 40 20 0 -6

-5

-4

-3

-2

-1

-3

-2

-1

log c

Ionophore 6

120

2+

Mg

100

Ca

2+

+

EMF / mV

K

80

Na

+

60 40 20 0

-6

-5

-4 log c

Fig. 6. Calibration plots of Mg2+ -selective electrodes based on ionophore 5 and 6 to sodium, potassium, magnesium and calcium.

67

Table 3 Potentiometric characteristics of magnesium ion-selective electrodes based on ionophore 5 and 6 Ionophore

5 6

Slopea

28.8 27.9 a b c

Detection limitb

Selectivity coefficientc Ca2+

K+

Na+

−5.2 −5.1

0.3 −0.2

−0.7 −1.0

−2.3 −2.9

Slopes from 10−5 to 10−1 M (mV per decade). log [Mg2+ ]. pot log kMg2+ ,j .

inferior to the malonic diamides attached to flexible alkyl chains [35–38]. These results suggest that the magnesium ion favors the better protected coordination sphere, and that the binding units introduced on rigid frame may not provide improved magnesium selectivity. 3.2. Anion-selective ionophores 3.2.1. Hydrogen bond-forming ionophores Recently, hydrogen bond-forming compounds have been proposed as effective anion-selective ionophores that can overcome the selectivity sequence given by Hoffmeister series: a partial list includes, lipophilic R− > ClO4 − > SCN− > I− > salycylate > NO3 − > Br − > Cl− > HCO3 − > SO4 2− > HPO4 2− . Some examples of hydrogen bond-forming ionophores are based on the compounds bearing guanidium, urea, and thiourea moieties [9–13], these functional groups are substituted proximally to anchoring molecular units, e.g., phenyl ring, nitrogen, and phorphyrin. Their anions selectivities are determined by the shape and distance between the hydrogen bond-forming moieties. To examine the anion selectivity modifying effect of rigid frame, we synthesized chenodeoxycholic acid derivatives substituted with urea and thiourea groups [42]. Three anion-selective ionophores 7, 8 and 9 were synthesized, and their potentiometric properties were examined using the PVC/NPOE and PVC/DOA matrices with and without cationic sites (TDMACl). As shown in Fig. 7a and b, the ionophore 7-based membranes with NPOE exhibits substantial anionic responses to most anionic species (e.g., SO4 2− , acetate, Cl− , Br− , NO3 − , HCO3 − ) over 10−3 M, even without cationic sites, but not with DOA plasticizer. This result indicates that the NPOE plasticized membrane, which has higher dielectric constant than the DOA plasticized, provides more favorable environment for distributing anions in the membrane phase. However, the magnitudes of the anionic responses were far from Nernstian without cationic sites, and exhibited even cationic response to the addition of sodium hydrogen phosphate. It was also noteworthy that the 7-based PVC/NPOE membrane exhibited higher selectivity to HCO3 − than NO3 − , which substantially deviates from the Hoffmeister series. The electrodes based on the ionophore 8 and 9 also resulted in similar potentiometric responses.

68

J.H. Shim et al. / Talanta 63 (2004) 61–71 150

300

(a) PVC / NPOE / Ionophore 7 100

200 -6

50

-4

EMF / mV

EMF / mV

10 M 10-5M

10 M -3

NaHPO4 Na2SO4 NaCl NaNO3 NaHCO3 NaSalicylate

0

-50

10 M

100 NaHPO4 NaHCO3 Na2SO4 NaCl NaNO3 NaSalicylate

0 -2

10 M

-100 -1

10 M

-100 0

100

200

300 400 Time, sec

500

600

700

-6

-5

-4

-3

-2

-1

log c

Fig. 8. Responses of the ionophore 8-based electrode to various anions: it exhibits well defined Nernstian response to sulfate ion (dotted line) from 10−6 to 10−1 M.

100 (b) PVC / DOA / Ionophore 7 50

EMF / mV

-1

10 M

0

-5

-6

-4

-2

-3

10 M 10 M 10 M 10 M

10 M

NaHPO4 Na2SO4 NaCl NaNO3

-50

-100

NaHCO3 NaSalicylate

-150 0

100

200

300 400 Time, sec

500

600

700

Fig. 7. Response curves of the electrodes based on ionophore 7 to various anions. PVC membranes with NPOE (a) and DOA (b) plasticizers are prepared without adding lipophilic cationic sites.

To increase the anionic responses of the ionophore 7-, 8and 9-based electrodes, the concentration of cationic sites in the membrane was varied from 10 to 100 mol%. The addition of cationic sites substantially increased the responses to most anionic species except to bicarbonate, and the reordered selectivity sequence close to Hoffmeister series. However, as shown in Fig. 8, the ionophore 8-based electrodes, especially the ones with 50 mol% cationic sites, exhibited greatly increased response to sulfate, resulting in

28.6 mV per decade of slope from 10−6 to 10−1 M. Bachas et al. observed that tris(2-aminoethylamine) functionalized with three urea groups exhibit enhanced sulfate recognition properties, as the tripodal urea groups provide preorganized binding cleft well suited for sulfate. We also reason that sulfate ions are extracted from the sample to membrane phase by cationic sites and well fit into the binding sites formed by the two thiourea functional groups terminated with phenyl. On the other hand, the electrodes based on ionophore 7 and 9, which have two urea functional groups, did not show enhanced sulfate selectivity. Table 4 summarizes the potentiometric behavior of the electrodes based on ionophore 7, 8 and 9: the general selectivity trend closely follows the Hoffmeister series with slight change in their order. We have synthesized various urea and thiourea functionalized cholic acid derivatives other than the ionophore 7–9. We have not included those compounds in this review as they all show very similar potentiometric properties, suggesting that the anion recognition through hydrogen bonding between the two urea or thiourea groups may not overcome the competitive ion-exchange by cationic sites (i.e., catalytic anion exchange by the quaternary ammonium salts in membrane phase). To develop anti-Hoffmeister anion-selective ionophores, we may need to design reversible covalent

Table 4 Potentiometric characteristics of anion-selective electrodes based on hydrogen bond-forming ionophore 7–9 Ionophore

Slopea

−57.7 −63.3 −62.7

7 8 9 a b

Detection limitb

−4.7 −4.6 −4.8

pot

Selectivity coefficient (log kCl− ,j ) HPO4 −

SO4 2−

OAc−

HCO3 −

Br−

NO3 −

SCN−

Sal−

ClO4 −

−2.9 −2.0 −2.1

−1.1 −0.1 −1.6

−1.5 −1.2 −1.4

−2.9 −1.1 −1.3

1.0 0.7 1.2

1.4 1.0 1.9

2.4 2.1 3.1

2.6 2.3 3.0

3.8 3.0 3.6

Slopes from 10−4 to 10−1 M (mV per decade). log [Cl− ].

J.H. Shim et al. / Talanta 63 (2004) 61–71

69

Table 5 Potentiometric characteristics of carbonate ion-selective electrodes based on ionophores 10–14 Ionophore

Slopea

−29.3 −27.6 −29.6 −18.5 −33.1

10 11 12 13 14 a b

pot

Selectivity coefficient (log kCO

Detection limitb

3

−5.4 −5.2 −5.6 −4.9 −5.5

2− ,j

Cl−

Br−

NO2

−5.2 −4.7 −5.7 −3.1 −5.8

−4.2 −3.9 −4.7 −3.6 −4.4

−3.5 −3.2 −3.8 −3.2 −3.7

)

−

NO3 −

SCN−

ClO4 −

Sal−

−3.0 −2.8 −3.3 −3.2 −3.4

−1.5 −1.3 −1.7 −2.0 −2.2

−0.8 −0.5 −0.9 −1.4 −1.2

−0.2 0.0 −0.3 −0.5 −0.8

Slopes from 10−5 to 10−1 M (mV per decade). log aCO3 2− .

bond-forming moieties or durable cationic centers modified to fit incoming guest anions.

have their TFAP groups on C3 and C12 positions, exhibited best carbonate selectivity. The distance between C3 and C12 is about 6 Å and larger than the optimal fitting size, ∼4.8 Å, of carbonate between two carbonyl carbons of two TFAP groups. To explain the discrepancy, we assumed that water molecule may participate in the carbonate binding between two TFAP groups of the ionophore 12 and 14, this proposition was partially supported by the FAB spectra of those compounds [21]. Of the cholic or deoxycholic acid-based TFAP derivatives, the electrode prepared with ionophore 14 exhibited the highest carbonate selectivity. Thus, we examined its practical utility for clinical analysis. To test the analytical accuracy of carbonate determination in serum in the presence of salicylate beyond therapeutic levels, potentiometric responses of the ionophore 14-based electrode to 10 times diluted sera containing 25 mM total carbon dioxide (TCO2 ) and 1–3 mM salisylate were measured. The carbonate selective membrane was prepared with the 7:3 blends of polyurethane and PVC to provide improved biocompatibility. The results of this experiment are shown in Fig. 9: the effect 3 mM of salicylate on the detection of 25 mM TCO2 in 10 times diluted serum was less than 6% higher value, and within the limit of potentiometric accuracy if the concentration of salicylate is below therapeutic level. It proves that the analytical performance

3.2.2. Covalent bond-forming ionophores TFAP group is one of the best known anion-recognizing moiety that binds carbonate through covalent bonding. Meyerhoff et al. showed that the TFAP derivatives normally forms stable 2:1 adduct with the carbonate ion in the presence of counter cations (e.g., tridodecylmethylammonium; TDMA+ ) [40]. Their observation led us to suppose that the carbonate-selective ionophores with two adjacent TFAP groups would provide enhanced carbonate selectivity, behaving like a molecular tweezers for the carbonate ion, and to design the compound with two or three TFAP groups on a rigid molecular scaffold [21–23]. As shown in Fig. 2, substituting two or three TFAP groups to the C3, C7 and C12 positions of the cholic or C3 and C12 positions of deoxycholic acid derivatives, four different cholic frame-based carbonate-selective ionophores, and one deoxycholic frame-based have been synthesized. Solvent polymeric carbonate-selective membranes have been prepared with the PVC (37.3 wt.%), DOA (57.5 wt.%), TFAP derivatives (5.2 wt.%), and TDMACl (40–50 mol%). Their potentiometric properties are summarized in Table 5. It is interesting to note that the ionophore 12 and 14, which

70 tCO2 2.5 mM

EMF / mV

80

tCO2 2.5 mM

-

Sal 0.1 mM

tCO2 2.5 mM -

Sal 0.2 mM

tCO2 2.5 mM -

Sal 0.3 mM

90 100 110

0

200

400

600 Time, sec

800

1000

1200

Fig. 9. Step response of the ionophore 14-based electrode to the 10 times diluted mixture of 25 mM carbonate and 0–3 mM salicylate.

70

J.H. Shim et al. / Talanta 63 (2004) 61–71 200

mV

(a)

160 155 150 145 140

Ionophore 14

180 pH 4.857

and faster than, while as accurate as, that obtained with the cumbersome potentiometric titration method.

(b)

4. Conclusion

EMF / mV

1mM

160

-4.4 7.314

-4.0

2mM

-3.6 Log aCO32-

3mM 4mM

7.587

140

7.684

TFADB

5mM 7.763 7.806

120

100 0

100

200

300 Time, sec

400

500

600

Fig. 10. Responses of the carbonate-selective electrodes based on ionophore 14 and trifluoroacetyl-p-decylbenzene (TFADB) to the step addition of carbonate in artificial seawater. Calibration line (b) is plotted based on the response in (a).

of new carbonate-selective ionophore is sufficient for clinical applications. We also examined the utility of the ionophore 14-based electrode for the determination of carbon dioxide in seawater, which contains very high level of interfering anions [23]. Fig. 10 shows the difference in the potentiometric responses of the ionophore 14- and TFADB-based electrodes to the change in TCO2 in artificial seawater that contains 0.6 M chloride and other interfering anions: only the ionophore 14-based electrode is quantitative to the change in TCO2 level. We then analyzed the TCO2 in real seawater, which was taken from Yellow Sea near to our laboratory, using the ionophore 14-based electrode. Table 6 shows the precision of the ionophore 14-based electrode in the analysis of real seawater, which can be compared to the results obtained with the Severinghaus-type gas electrode, and conventional potentiometric titration method. The whole analytical procedure with the ionophore 14-based electrode was much easier

Table 6 Determination of total carbon dioxide in Yellow Sea with ionophore 14-based electrode ISE sample no.

TCO2 value determined

E1 E2 E3 E4 E5

1.92 1.99 1.93 1.94 1.93

Mean value CO2 gas sensor Potentiometric titration

1.94 ± 0.07 (n = 5) 1.93 ± 0.01 (n = 3) 1.95 ± 0.04 (n = 8)

We summarized our recent efforts on the potentiometric characterization of cholic, deoxycholic, and chenodeoxycholic acid derivatives substituted with various ion-recognizing moieties. The dithiocarbamete and bipyridyl group containing ionophores 1 and 2, respectively, exhibit high silver ion selectivity. Especially, the ionophore 1-based electrode could detect 100 ppt level of silver ion, if the composition of its internal filling solution is used as Prescribed by Pretsch et al. The cholic acid derivatized with glycolic diamides exhibited high calcium selectivity, but its complex formulation constant was 105 times smaller than that of ETH 1001. It was proposed that the calcium binding units fixed on rigid scaffold have limited freedom in reorganizing themselves for optimal configuration about the calcium ion, resulting in a weaker complex. However, the reduced calcium binding ability of the ionophore 14 was advantageous for eliminating anionic interference: the electrode exhibited extended linear response up to 0.1 M even in the presence of strongly lipophilic anions, e.g., percholorate, thiocyanate, salicylate, and iodide. The cholic acid derivatized with two or three malonic diamides exhibited substantially increased magnesium selectivity. Although their magnesium selectivity over pot calcium (k 2+ 2+ ) was less than 0.5, the bi- and tripoMg ,Ca dal malonic diamides may find their analytical uses in water hardness determination. Anion-selective ionophores 7, 8 and 9 have been designed by substituting urea and thiourea group containing chains to the hydroxyl linkers of chenodeoxycholic acid frames. The urea or thiourea derivative-based solvent polymeric membranes plasticized with NPOE exhibited anionic responses even without added cationic sites, confirming their anion recognizing ability through hydrogen bonding between the two parallel urea or thiourea groups. Addition of mobile cationic sites greatly increased the anionic responses of the ionophores 7–9-based electrodes. However, their selectivity closely followed the sequence of Hoffmeister series, except the unusually large response of the ionophore 8-based electrode to sulfate. The most successful examples of cholic or deoxycholic acid frame-based ionophores are those functionalized with two carbonate-selective TFAP groups. Experimental results reveal that bipodal substitution of TFAP groups on C3 and C12 positions of cholic and deoxycholic acid scaffold, whose centers are about 6 Å apart, yields the ionophores with highest carbonate selectivity over other anions. Carbonate ion forms covalent bonding directly with at least one electro deficient carbonyl carbon of TFAP, and possibly a hydrogen bonding with the intervening water molecule attached to the other carbonyl center of TFAP; i.e., bipodal TFAP

J.H. Shim et al. / Talanta 63 (2004) 61–71

groups behaves like a tweezers for the incoming carbonate. We demonstrated that the carbonate-selective electrodes prepared with the ionophore 14, which have bipodal TFAP on deoxycholic acid frame, exhibit analytically interference free and quantitative responses to the carbonate in serum and seawater samples. In this article, we have shown that the new cholic acid frame-based ionophores are as versatile as those based on calixarene frame. We are attempting to introduce various ion-recognizing moieties to the rigid cholic or deoxycholic acid derivatives other than those discussed in this article, expecting to find new ionophores with enhanced potentiometric properties.

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