Design and Synthesis of a More Highly Selective Ammonium

Wei Zhang, Ewa Rozniecka, Elzbieta Malinowska, Pawel Parzuchowski, and Mark E. Meyerhoff. Analytical Chemistry 2002 74 (17), 4548-4557. Abstract | Ful...
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Anal. Chem. 2000, 72, 2200-2205

Design and Synthesis of a More Highly Selective Ammonium Ionophore Than Nonactin and Its Application as an Ion-Sensing Component for an Ion-Selective Electrode Koji Suzuki,*,†,‡ Dwi Siswanta,† Takeshi Otsuka,† Tsuyoshi Amano,† Takafumi Ikeda,† Hideaki Hisamoto,†,| Ryoko Yoshihara,§ and Shigeru Ohba§

Department of Applied Chemistry and Department of Chemistry, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan, and Kanagawa Academy of Science and Technology (KAST), KSP West-614, 3-2-1 Sakato, Kawasaki 213-0012, Japan

A novel ammonium ionophore, which exhibits superior NH4+ selectivity compared with that of the natural antibiotic nonactin, was successfully designed and synthesized based on a 19-membered crown compound (TD19C6) having three decalino subunits in the macrocyclic system. This bulky decalino subunit is effective for (1) increasing the structural rigidity of the cyclic compound, (2) introducing the “block-wall effect”, which prevents forming a complex with a large ion, and (3) increasing the lipophilicity of the ionophore molecule. In the ammonium ionophore design, the first factor contributes to increasing the NH4+ selectivity relative to smaller ions such as Li+, Na+, or even the closest size, K+, and the second factor increases the NH4+ selectivity over larger ions such as Rb+ and Cs+. The X-ray structural analysis proved that TD19C6 forms a size-fit complex with NH4+ in its crown ring cavity. As an application of this ionophore, an ion sensor (ion-selective electrode) was prepared, which exhibited NH4+ to K+ and Na+ selectivity of 10 and 3000 times, respectively. This electrode showed a better performance compared to the electrode based on nonactin, which is the only ammonium ionophore presently used in practical applications. The availability of a highly selective ammonium ionophore is crucial for the preparation of ammonium ion chemical sensors and biosensors used for the direct measurement of the ammonium ion1-10 as well as ammonium-derived urea,11-15 amines,16,17 or †

Department of Applied Chemistry, Keio University. Kanagawa Academy of Science and Technology (KAST). § Department of Chemistry, Keio University. | Present address: Department of Applied Chemistry, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8566. (1) Ghauri, M. S.; Thomas, J. D. R. Analyst 1994, 119, 2323. (2) Thanei-Wyss, U.; Morf, W. E.; Lienemann, P.; Stefanac, Z.; Mostert, I.; Dorig, R.; Dohner, R. E.; Simon, W. Mikrochim. Acta 1983, Ill, 135. (3) Ma, S. C.; Chaniotakis, N. A.; Meyerhoff, M. E. Anal. Chem.1988, 60, 2293. (4) Beer, D. De.; van den Heuvel, J. C. Talanta 1988, 35, 728. (5) Fresser, F.; Moser, H.; Nair, M. J. Exp. Biol. 1991, 147, 227. (6) Henriksen, G. H.; Bloom, A. J.; Spanswick, R. M. Plant. Physiol. 1990 93, 271. (7) Seiler, K.; Morf, W. E.; Rusterholz, B.; Simon, W. Anal. Sci. 1989. 5, 557. ‡

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ammonia.18,19 Until recently, the only available practically used ammonium ionophore was nonactin, a natural product, which was first employed as the ion-sensing component for an ammonium ion-selective electrode in 1970.20 For many other ions, following the use of natural products as ionophores, many researchers designed and synthesized highly selective synthetic ionophores for an objective ion, but there are no practically successful ionophores for NH4+ except nonactin.21,22 Previously, we reported the synthesis of novel ammonium ionophores based on glycol benzyl ether derivatives,9,23 which showed a relatively high ammonium ion selectivity toward K+, but their NH4+-to-Na+ ratios were not sufficient for practical use when utilized as the ionsensing component for an ammonium ion-selective electrode. A similar result was obtained with a pyrazol-containing crown ether derivative by Moriuchi-Kawakami et al.10 Here we report the first successfully designed and synthesized ammonium ionophore more highly selective than nonactin. Most of the useful ionophores for alkali and alkaline earth metal ions are based on a crown ether cyclic structure; therefore, (8) Knoll, M.; Cammann, K.; Dumschat, C.; Sunder-meier, C.; Eschold, J. Sens. Actuators 1994, B18-19, 51. (9) Siswanta, D.; Hisamoto, H.; Tohma, H.; Yamamoto, N.; Suzuki,K. Chem. Lett. 1994, 945. (10) Moriuchi-Kawakami, T.; Nakazawa, S.; Ota, M.; Nishihara, M.; Hayashi, H.; Shibuyani, Y.; Shono, T. Anal. Sci. 1988, 14, 1065. (11) Schindler, J. G. Eur. J. Clin. Chem. Clin. Biochem. 1994, 32, 145. (12) Alegret, S.; Bartoli, J.; Jimenez, C.; Martinez-Fabregas, E.; Martorell, D.; Valdes-Perezgasga, F. Sens. Actuators 1993, B15-16, 453. (13) Vaillo, E.; Walder, P.; Spichiger, U. E. Anal. Methods Instrum. 1995, 2, 145. (14) Borchardt, M.; Dumschat, C.; Cammann, K. Sens. Actuators 1995, B2425, 721. (15) Stamm, C.; Seiler, K.; W. Simon Anal. Chim. Acta 1993, 282, 239. (16) Odashima, K.; Yagi, K.; Tohda, K.; Umezawa, Y. Anal. Chem. 1993, 65, 1074. (17) Chan, W. H.; Lee, A. W. M.; Wang, K. Analyst 1994, 119, 2809. (18) Ozawa, S.; Hauser, P. C.; Seiler, K.; Tan, S. S. S.; Morf, W. E.; Simon, W. Anal. Chem. 1991, 53, 640. (19) West, S. J.; Ozawa, S.; Seiler, K.; Tan, S. S. S.; Simon, W. Anal. Chem. 1992, 54, 633. (20) Scholer, R. P.; Simon, W. Chimia 1970, 24, 372-374. (21) Umezawa, Y. Handbook of Ion-Selective Electrodes: Selectivity Coefficients; CRC Press: Boca Raton, FL, 1990. (22) Buhlmann, P.; Bakker, E.; Pretch, E. Chem. Rev. 1998, 98, 1593. (23) Suzuki, K. J. Synth. Org. Chem. Jpn. 1998, 56, 291. 10.1021/ac9911241 CCC: $19.00

© 2000 American Chemical Society Published on Web 04/06/2000

Figure 1. Effective molecular structure design for ammonium ionophore (target ion, NH4+).

Potassium ion and ammonium ion have a similar ionic size, but considering the hydrogen-bonding distance of K+‚‚‚O and N-H‚‚‚O, the latter bond is slightly longer. Consequently, NH4+ has a slightly larger ionic size than that of K+. Because 18-crown-6 is the best fit for K+ in its cavity, we then designed a larger size of crown ether using 19-crown-6 as the backbone. Based on the molecular model shown in Figure 1, three ionophores using a 19-crown-6 structure shown in Figure 2 were synthesized. As a result, TD19C6, which possessed three decalino subunits in the 19-membered crown ring, exhibited a high ammonium ion selectivity toward other alkali metal and alkaline earth metal ions. This ammonium ion selectivity is better than that of nonactin.

Figure 2. Chemical structures of the newly synthesized ammonium ionophores (TD19C6, DD19C6, TTM19C6) which have a 19membered-crown ring with three or two bulky block subunits and nonactin.

a major obstacle exists in employing a normal crown ether for designing an ammonium ionophore because the ammonium ion has an ionic size similar to that of K+.23 We now introduce two major and unique factors to be considered when designing an ammonium ionophore based on a crown ether basic structure, i.e., introducing a rigid frame and “block-walls” in the macrocyclic structure, preventing the formation of both a wrapping complex of the crown ether with a smaller ion and a sandwich complex with a larger ion, as demonstrated in Figure 1. We selected a decalino subunit (derived from decalin diol 1) to satisfy both the requirements of rigidity and the “block-wall effect” and incorporate it into the macrocyclic system. For a comparative study, a tetramethylethano-subunit (derived from pinacol) was also used as the “block” subunit, and highly lithium and sodium ion-selective ionophores were successfully obtained.24,25 (24) Suzuki, K.; Yamada, H.; Sato, K.; Watanabe, K.; Hisamoto, H.; Tobe, Y.; Kobiro, K. Anal. Chem. 1993, 65, 3404. (25) Suzuki, K.; Sato, K.; Hisamoto, H.; Siswanta, D.; Hayashi, K.; Kasahara, N.; Watanabe, K.; Yamamoto, N.; Sasakura, H. Anal. Chem. 1996, 68, 208.

EXPERIMENTAL SECTION Reagents. The highest grade commercially available reagents were used for the syntheses of the new compounds and the preparation of the aqueous test electrolytes. The distilled and deionized water used had a resistivity of greater than 1.5 × 107 Ω cm at 25 °C. The electrode membrane solvent bis(1-butylpentyl) adipate (BBPA) was purchased from Fluka AG, Buchs, Switzerland. Poly(vinyl chloride) (PVC, high molecular weight type) used as the electrode membrane material was obtained from Sigma, Chemical Co. (St. Louis, MO). Synthesis of 19-Crown-6 Derivatives. 2,5,12,15,22,26Hexaoxaheptacyclo[25.4.4.46.11416.21.01.27.06.11.016.21]tritetracontane (TD19C6). A solution of cis-1,6-dihydroxybicyclo[4.4.0]decane (10 g, 58.7 mmol), malonaldehyde bis(dimethylacetal) (4.778 g, 29.1 mmol), and p-toluenesulfonic acid (0.477 g) in benzene (50 mL) was refluxed for 2 h. The reaction mixture was then evaporated and partitioned three times with chloroform. The chloroform was then evaporated. The residue was dissolved in a small amount of chloroform (20 mL), methanol (20 mL) was then added, and the solution cooled at 0 °C for 2 h. The resulting white crystals were filtrated, separated, and identified as 12,12′-methylenedi-11,13-dioxatricyclo[4.4.3.01.6]tridecane (product 1, 8.74 g, 79.8%). A solution of lithium aluminum hydride (1.586 g, 41.8 mmol) in ether was added to the solution of aluminum chloride (22.29 g, 167.2 mmol) in ether, and the mixture stirred in a water bath for 30 min. Product 1 was then added and stirred for 3 h. After Analytical Chemistry, Vol. 72, No. 10, May 15, 2000

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the addition of water followed by the addition of a 10% H2SO4 solution, the solvent was decanted and the water phase was extracted three times with ethyl acetate. The organic solvent was evaporated, and the obtained residue was purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to yield 6,6′-(propylenedioxy)di-cis-1-hydroxydecane (product 2, 7.13 g, 85.2%) as a white solid. Chloroacetic acid (5.76 g, 60.93 mmol) was added to a mixture of cis-1,6-dihydroxybicyclo[4.4.0]decane (2.0 g, 25.39 mmol) and NaH (4.06 g, 101.5 mmol) in 100 mL of THF and the resultant mixture refluxed for 16 h. After the addition of methanol (10 mL), the solvent was evaporated and 50 mL 1 M HCl was added to the residue and partitioned three times with chloroform. The organic layer was dried over Na2SO4 and the solvent evaporated to obtain cis-1,6-di(3′-oxapropionic acid)bicyclo[4.4.0]decane (3). Product 3 was then dissolved in 100 mL of ethanol-benzene (1:1), and 3A molecular sieves (50 mg) and p-toluensulfonic acid (0.13 g) were added to the solution. The reaction mixture was refluxed at 90 °C for 17 h, and the organic solvent was then evaporated. The residue was dissolved in 100 mL of ethyl acetate and washed with aqueous NaHCO3 and brine. The organic phase was evaporated, and the residue was purified by silica gel column chromatography (hexanes-ethyl acetate 2:1) to obtaincis-1,6-di(3′-oxaethoxypropanoyl)bicyclo[4.4.0]decane (4, 2.8 g, 69.6%). Product 4 (3.2 g, 9.34 mmol) was added to a solution of LiAlH4 (1.03 g, 27.79 mmol) in 30 mL of THF and refluxed for 25 h. After the addition of methanol (20 mL), the organic solvent was evaporated and the residue was partitioned three times with ethyl acetate. After evaporation of ethyl acetate, the resulting residue was purified by silica gel column chromatography to give cis-1,6di-(2′-hidroxyethoxy)bicyclo[4.4.0]decane (5, 0.7 g, 28.99%). Product 5 (0.7 g, 2.71 mmol) was dissolved in 10 mL THF, pyridine (20 mL) was then added, and the mixture was stirred on an ice bath for 45 min. A solution of tosyl chloride (1.29 g, 6.77 mmol) in 30 mL THF was then slowly added, and the reaction mixture was stirred for 5 h. After evaporation of the organic phase, the residue was dissolved in chloroform and washed with HCl solution (pH 1) and brine. The chloroform was evaporated and the residue was purified by silica gel chromatography (hexanesethyl acetate 4:1) to give cis-1,6-di-(2′-hidroxyethoxytosylate)bicyclo[4.4.0]decane (6, 0.85 g, 55%). NaH (141 mg, 11 mmol) was added to the solution of 2 (335.8 mg, 0.88 mmol) in THF (20 mL) and the resultant mixture stirred for 1 h at 40 °C. A solution of 6 (500 mg, 0.88 mmol) in 30 mL of THF was then added to this mixture. The mixture was then stirred at 70 °C for 6 days. A small amount of methanol (10 mL) was added to quench the excess NaH. After evaporation of the THF, the residue was extracted twice with ethyl acetate. The organic phase was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl yield TD19C6 (9 mg, 1.7%) as white crystals. 1H NMR (270 MHz, CDCl3) δ 1.252.35 (m, 50H, CH2), 3.3-4.1 (m, 12 H, OCH2). Anal. Calcd for C37H62O6(602.89): C, 73.71; H, 10.36. Found: C, 73.32; H, 10.56. (2,6,13,16,19,22-Hexaoxapentacyclo[21.4.4.1.2347.121.23 0 .07.12]pentatriacontane (DD19C6). Mesyl chloride (8.01 g, 69.9 mmol) was added to a solution of triethylene glycol (5.0 g, 33.3 mmol) in 50 mL of stirred pyridine in an ice bath. This reaction mixture was stirred for 5 h. After evaporation of the 2202

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organic phase, the residue was dissolved in chloroform and washed with HCl solution (pH 1) and brine. The chloroform was evaporated, and the residue was purified by silica gel chromatography (hexanes-ethyl acetate 4:1) to give 7 (2.03 g, 19.9%). NaH (200 mg, 5 mmol) was added to the solution of product 2 (267.5 mg, 0.87 mmol) in THF (20 mL) and stirred for 1 h at 40 °C. A solution of 7 (267.5 mg, 0.87 mmol) in 30 mL of THF was then added to this mixture. The mixture was stirred at 70 °C for 20 h. A small amount of methanol (10 mL) was added to quench the excess NaH. After evaporation of the THF, the residue was extracted twice with ethyl acetate. The organic phase was then evaporated, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 3:1) and further purification using HPLC with acetone as the eluent to yield DD19C6 (12 mg, 2.8%) as a colorless oil:1H NMR (270 MHz, CDCl3) δ 1.18-2.18 (m, 34H, CH2), 3.20-4.05 (m, 16 H, OCH2). Anal. Calcd for C29H50O6(494.36): C, 70.41; H, 10.19. Found: C, 70.02; H, 10.29. 2,2,3,3,8,8,9,9,14,14,15,15-Dodecamethyl-1,4,7,10,13,16-hexaoxacyclononadecane (TTM19C6). To a solution of pinacol (7.27 g, 61.5 mmol) and malonaldehyde bis(dimethylacetal) (5.0 g, 30.45 mmol) in benzene (150 mL) was added a catalytic amount of p-toluenesulfonic acid monohydrate (100 mg), and the resultant mixture was stirred at 90 °C for 2 h. The reaction mixture was then evaporated and partitioned three times with chloroform. The organic phase was evaporated, and the residue was purified by silica gel column chromatography with hexaneethyl acetate (4:1) to yield 2,2-methylenedi-4,4,5,5-tetramethyl-1,3dioxolane (product 8, 7.87 g, 95.0%) as white crystals. A solution of lithium aluminum hydride (752 mg, 19.8 mmol) in 10 mL of ether was added to the solution of aluminum chloride (10.57 g, 79.3 mmol) in 130 mL of ether, and the resultant mixture stirred in a water bath for 30 min. The product 8 (3.0 g, 11 mmol) was then added and stirred for 3 h. After the addition of water followed by addition of 10% H2SO4 solution (25 mL), the organic phase was decanted and the water phase was extracted three times with ethyl acetate. The organic phase was collected and evaporated. The obtained residue was purified by silica gel column chromatography with hexane-ethyl acetate (1:1) as the eluent to yield 2,3,3,9,9,10-hexamethyl-4,8-dioxa-2,10-undecanediol (product 9, 2.46 g, 80.9%) as a white solid. Chloroacetic acid (5.76 g, 60.93 mmol) was added to a mixture of pinacol (3.0 g, 25.39 mmol) and NaH (4.06 g, 101.5 mmol) in 100 mL of THF and refluxed for 16 h. After the addition of methanol (10 mL), the solvent was evaporated and then 50 mL of 1 M HCl was added to the residue and partitioned three times with chloroform. The organic phase was dried over Na2SO4 and evaporated to obtain 3,3,4,4-tetramethyl-2,5-dioxa-1,6-hexanedioic acid (10). The product 10 was then dissolved in 100 mL of ethanol-benzene (1:1), and molecular sieves 3A (50 mg) and p-toluenesulfonic acid (0.13 g) were added to the solution. The reaction mixture was refluxed at 90 °C for 17 h, and then the organic solvent was evaporated. The residue was dissolved in 100 mL of ethyl acetate and washed with aqueous NaHCO3 and brine. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexanes-ethyl acetate 2:1) to obtain 3,3,4,4-tetramethyl-2,5-dioxa-1,6-hexanedioic acid diethyl ester (11, 2.33 g, 31.6%).

Product 11 (3.2 g, 9.34 mmol) was added to a solution of LiAlH4 (1.03 g, 27.79 mmol) in 30 mL of THF and refluxed for 25 h. After the addition of methanol (20 mL), the organic solvent was evaporated and the residue was partitioned three times with ethyl acetate. After evaporation of the ethyl acetate, the resulting residue was purified by silica gel column chromatography to give 4,4,5,5-tetramethyl-3,6-dioxa-1,8-octanediol (12, 0.82 g, 49.25%). Product 12 (0.82 g, 1.5 mmol) was dissolved in 10 mL of THF, pyridine (20 mL) was then added, and the mixture was stirred in an ice bath for 45 min. A solution of tosyl chloride (0.71 g, 3.74 mmol) in 30 mL of THF was then added slowly, and the reaction mixture was stirred for 5 h. After evaporation of the organic phase, the residue was dissolved in chloroform and washed with HCl solution (pH 1) and brine. The chloroform was evaporated, and the residue was purified by silica gel chromatography (hexanesethyl acetate 4:1) to give 13 (1.19 g, 58.57%). NaH (135 mg, 10.6 mmol) was added to the solution of product 9 (238 mg, 0.86 mmol) in THF (20 mL), and the resultant mixture stirred for 1 h at 40 °C. A solution of 13 (450 mg, 0.88 mmol) in 30 mL of THF was then added. The mixture was then stirred at 70 °C for 3 days. A small amount of methanol (10 mL) was added to quench the excess NaH. After evaporation of the THF, the residue was extracted twice with ethyl acetate. The organic phase was then evaporated, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4:1) and further purification using HPLC with acetone as the eluent to yield TTM19C6 (18.2 mg, 4.7%) as a colorless oil: 1H NMR (270 MHz, CDCl3) δ 1.14-1.15 (d, J ) 4.34 Hz, 36H, CH3), 1.63-1.69 (t, 2 H, CH2), 3.37-3.57 (m, 12H, OCH2). Anal. Calcd for C25H50O6(446.67): C, 67.23; H, 11.28. Found: C, 67.02; H, 11.49. The lipophilicity (log po/w, the partition coefficient of oil and water) of the newly synthesized ionophores was measured according to a previously reported procedure.26 X-ray Crystal Structure Analysis. The X-ray crystallographic analysis for TD19C6 was performed using an AFC-7R analyzer (Rigaku-Denki Co., Ltd., Tokyo, Japan). The single-crystal sample was obtained by recrystallization of the TD19C6-NH4+SCNcomplex with acetone. The detailed crystallographic data for TD19C6 are described in the Supporting Information. Electrode Membrane Preparation and EMF Measurements. For the potentiometric studies, the newly synthesized ionophores (TD19C6, DD19C6, TTM19C6) were then incorporated in a polymeric membrane electrode using the KTCPB previously reported procedures. The membrane composition was 3 wt % ionophore, 10 mol % (relative to the ionophore) anionic additive (tetrakis(p-chlorophenyl) borate potassium salt, KTCPB), 67 wt % membrane solvent, BBPA), and 30 wt % PVC (high molecular weight). The membrane thickness was ∼100 µm. A 6-mm-diameter circle was cut from a prepared membrane and placed on the tip of the ion-selective electrode body assembly. The prepared electrodes were immersed in 0.1 M NH4Cl solution for over 24 h for preconditioning before use. The electrode response potential (emf) measurements were performed according to the reported procedure at 25 ( 0.5 °C using the electrochemical cell system.27 (26) Dinten, O.; Spichger, U. E.; Chaniotokis, N.; Gehrig, P.; Rusterholz, B.; Morf, W. E.; Simon, W. Anal. Chem. 1991, 63, 596. (27) Suzuki, K.; Tohda, K.; Aruga, H.; Matsuzoe, M.; Inoue, H.; Shirai, T. Anal. Chem. 1988, 60, 1714.

Ag|AgCl|3 M KCl||test solution|membrane| 0.1 M NH4Cl|AgCl|Ag All test solutions were made from the chloride salt without any pH-adjusting buffer reagent. The selectivity coefficients, Kijpot, where i is the primary ion (NH4+) and j is the interfering ion, were calculated from the response potentials in an alkali metal or alkaline earth metal chloride solution using the separate solution method (SSM, i ) j ) 0.1 M) according to the recommendations of the IUPAC and JIS.28,29 RESULTS AND DISCUSSION As described in the introduction, the aim of the present investigation was to obtain a higher NH4+-selective ionophore compared to that of nonactin that was designed on the basis of a molecular model involving a bulky block-wall and rigid subunits, as shown in Figure 1. The structures of our synthesized NH4+ ionophore (Figure 2) are TD19C6, DD19C6, and TTM19C6 containing two or three decalino or tetramethylethano subunits as the block-wall subunits in their basic skeleton of the 19 -membered crown 6. Regarding the synthesis of these ionophores, the overall synthetic yields of these 19-membered cyclic compounds were low because the reaction with the highly hindered tertiary alcohols were utilized in their synthesis. However, implementing efficient procedures for the synthesis of important decalino units of 6,6′(propylenedioxy)di-cis-1-hydroxydecane (2) by Sachleben et al.30 and product 5 by Kobiro et al.,31 then the only low-yield reaction (∼10% yield) was the final coupling using product 2 and the ditosylate of product 5. The synthesis work involving the tetramethyl subunit for the preparation of TTM19C6 gave a higher overall yield, but in our experience, the product, which has a higher final coupling yield, showed a lower block effectivity and structural rigidity compared to the decaline diol unit. Furthermore, the tetramethyl subunit exhibited a lower contribution to the lipophilicity of the ionophore, which is an important parameter for application of the ionophore as a sensory molecule in an ionselective electrode membrane. The typical lipophilicity parameter, log po/w, of the ionophores is 13.5 ( 0.7 for TD19C6 and 12.2 ( 0.6 for DD19C6, which possess three and two decalino subunits, respectively, while the log po/w of TTM19C6, which has three tetramethyl subunits, is 7.9 ( 0.6 and that for nonactin is 5.8 ( 0.4. Consequently, the decalino subunits incorporated in the 19crown-6 backbone structure (TD19C6) finally have the three roles of rigidity, “block-wall effect”, and added lipophilicity to the ionophore molecule. The selectivity coefficients of the NH4+ electrodes based on TD19C6, DD19C6, TTM19C6, and nonactin are shown in Figure 3. The electrode based on TD19C6 exhibited high selectivity relative to alkali metal and alkaline earth metal ions, especially to K+ and Na+, which are the major sources of interferences in the sensing of NH4+. The ionic selectivity pattern was NH4+ > K+ > (28) IUPAC Recommendation for Nomenclature of Ion-Selective Electrodes. Pure Appl. Chem. 1976, 48, 29. (29) JIS K-0122, Japanese Standards Association, Tokyo, 1997. (30) Sachleben, R. A.; Davis, M. C.; Bruce, J. J.; Ripple, E. S.; Driver, J. L.; Moyer, B. A. Tetrahedron Lett. 1993, 34, 5373. (31) Kobiro, K.; Ohnishi, K.; Kakiuchi, K.; Tobe, Y.; Odaira, Y. Bull. Chem. Soc. Jpn. 1985, 58, 1333.

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Figure 3. Selectivity coefficients of the ammonium ion-selective electrodes based on TD19C6, DD19C6, TTM19C6, and nonactin. The membrane compositions for the three ionophores based on 19C6 derivatives were 3 wt % ionophore, 10 mol % (of the ionophore content) KTCPB, 67 wt % BBPA, and ∼30 wt % PVC. The ion-selectivity factors of the nonactin-based electrode were obtained from ref 9.

Rb+ > Cs+ > Na+ > Mg2+ > Ca2+. When a normal 19-crown-6 without block subunits is used, it would be hard to obtain a high ability to differentiate NH4+ from K+ and Rb+, because the normal crown compound is flexible enough to accommodate ions with similar sizes. A very attractive fact for TD16C5 is that Na+, which is smaller than NH4+, is strongly rejected. In addition, Cs+, which is larger compared to NH4+, was also strongly discriminated. Some typical electrode membrane solvents such as BBPA, 2-nitrophenol octyl ether, (NPOE), and tris(2-ethylhexyl phosphate) (TEHP) were used and examined for ion selectivity with the electrode based on TD19C6. The best results in the NH4+ selectivity against Na+ and K+ were obtained in the case where BBPA, which has an low dielectric constant ( ) 4; where  is dielectric constant), was used as the membrane solvent. For the anionic additive (TCPB anion) composition, the best results for NH4+ selectivity were obtained where the TCPB used was 1040mol % against the ionophore content in the electrode membrane. The electrode based on DD19C6, which possesses two decalino subunits, showed NH4+/K+ and NH4+/Na+ selectivities of -0.24 and -2.23, respectively. These selectivity values indicate that TD19C6 has a higher ring rigidity and block-wall effect than those with DD19C6. With only two blocking subunits, the triethylene glycol subunit is an open and flexible segment which reduces the NH4+ selectivity of DD19C6. The drastic lowering of the NH4+to-Na+ selectivity rather than the decreasing of the Cs+ selectivity should indicate that the decreasing of the structural rigidity of DD19C6 was more dominant than the decreasing of the blockwall effect for larger size ions. The electrode based on TTM19C6, which has three tetramethylethano subunits, exhibited NH4+/K+ and NH4+/Na+ selectivities of -0.66 and -2.82, respectively. Overall, regarding the ionic selectivity of the electrode based on TD19C6, the tetramethylethano subunit is inferior in terms of increasing the rigidity of the crown structure and also in terms of the effectivity in producing the block-wall effect compared to the decalino subunit. 2204 Analytical Chemistry, Vol. 72, No. 10, May 15, 2000

Figure 4. Steric chemical structures of TD19C6-NH4+ complex determined by X-ray analysis.

We have successfully designed and synthesized highly selective Li+ and Na+ ionophores by introducing one and two decalino subunits in a 14-crown-4 and 16-crown-5, respectively.24,25 In the present investigation, introducing three decalino subunits in a 19crown-6 resulted in a significant breakthrough in designing a highly selective ammonium ionophore, because K+ and NH4+ are strikingly difficult to discriminate. In our previous study, a relatively rigid and blocked podand-type glycol benzyl ether exhibited a high ammonium-to-K+ selectivity, but it failed to improve the rejection of Na+.18 The present work has overcome this problem. The ammonium complex structure determined by threedimensional X-ray analysis showed that only three of four hydrogen atoms of the ammonium ion coordinate with six oxygen atoms in the crown as shown in Figure 4, thus leaving one hydrogen atom free in the upward direction relative to the crown ring plane, which is normally coordinated to a counteranion. The determined steric structure of TD19C6 proved that the ionophore molecule forms a size-fit complex with NH4+ in its crown ring

cavity which was a satisfactory result that we expected in the design stage. The NH4+/K+ and NH4+/Na+ selectivities of the electrode based on TD19C6 were -1.00 and -3.52, respectively. Although this electrode exhibited a similar NH4+/K+ selectivity compared with the selectivity of the electrode based on nonactin, it showed a very drastic improvement in ammonium selectivity over Na+ (∼10 times). The electrode based on TD19C6 showed a response to ammonium ions in the activity range of 5 × 10-6-10-1 M NH4+ in an almost Nernstian response (the average slope obtained with five electodes using TD19C6 was 58.1 mV/activity decade). The electrode response slope and selectivity were very similar to the values during the first day of use. In conclusion, this is the first case of obtaining a highly ammonium ion-selective ionophore, TD19C6, which exhibits superior NH4+ selectivity compared to that of nonactin. Thus, TD19C6 is the best ammonium ionophore developed to date. The designing of an ionophore based on a unique concept that involves reducing the coordinating ability with interfering ions other than the objective ion by using “block” subunits was demonstrated in

the present report. This molecular design concept opens the way to obtaining highly analyte-selective ionophores and practically useful ion sensors. ACKNOWLEDGMENT Partial support of this investigation by the Kanagawa Academy of Science and Technology and the Ministry of Science and Technology is acknowledged. This study was also partially supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture. SUPPORTING INFORMATION AVAILABLE The X-ray crystallographic analysis data for TD19C6. This material is available free of charge via the Internet at http:// pubs.acs.org.

Received for review September 29, 1999. Accepted February 8, 2000. AC9911241

Analytical Chemistry, Vol. 72, No. 10, May 15, 2000

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