Anal. Chem. 1985, 57, 493-495 493 require the use of an alkali metal compound. Also mass spectrometric studies demonstrate tha t the negative ion species CN-, PO-, POz-, and PO3- are prominently formed when nitrogen and phosphorus compounds impact the surface of the LaB,/SiO, bead in the vacuum environment of a mass spectrometer ion source. These mass spectrometric data are consistent with prior speculations that these specific ion species are also formed in the TID environment. ACKNOWLEDGMENT I am grateful t o D. S. Linton a t Yokota Air Base for the manuscript preparation procedure. Registry No. LaB,, 12008-21-8; SOz , 7631-86-9. LITERATURE CITED (3) Lubkowitz, J. A.; Semonian, B. P.; Galobardes, J.; Rogers, L. B. Anal. Chem. 1978, 50, 672. (4) Patterson, P. L.; Howe, R. L. J . Chromatogr. Sci. 1978, 16. 275. (5) Karmen, A.: Guiffrida, L. E. Nature (London) 1964, 201, 1204. (6) Farwell, S. 0.; Gage, D. R.; Kagel, R. A. d . Chromafogr. 1981, 19, 358. (7) Kolb, B.; Auer, M.; Pospisil, P. J . Chromafogr. Sci. 1977, 15, 53. (8) Franklin, J. L.; Harland. P. W. Annu. Rev. Phys. Chem. 1974, 25, 485. (9) Reader, J.; Corliss. C. H. In “CRC Handbook of Chemistry and Physics”; Weast, R. C., Ed.; CRC Press: Boca Raton, FL, 1979/1980; IO) Brazhnikov, V. V.: Gurev. M. V.; Sakodynsky, K. I. Chromatogr. Rev. 1980, 72, 1. 11) Patterson, P. L. J . Chromatogr. 1976, 167, 381. 12) Olah, K.; Szoke, A.; Vajta, Zs. J . Chromatogr. Sci. 1979, 17, 497. 13) Moon, P. B. Proc. Cambridge Philos. Soc. 1932, 28, 490. 14) Lazarev, V. B.; Malov, Y. I. Fiz. Met. Metalloved. 1967, 24. 565. 15) Lafferty, J. M. J . Appl. Phys. 1951, 22, 299. 16) Fujii, T. I n t . J . Mass Spectrom. Ion Processes 1984. 57, 63 17) Fujii, T. J . Phys. Chem. 1984, 88, 5228. p E-303. (1) Kolb, B.; Bishoff, J. J . Chromafogr. Sci. 1974, 12. 625. (2) Burgett, C. A,; Smith, D. H.; Bente, H. B. J . Chromatogr. 1977, 134, 57. 11, 1984. Accepted October 22, 1984. RECEIVED for review July 12, 1984. Resubmitted September Lipophilic Lithium Ion Carrier in a Lithium Ion Selective Electrode Victor P . Y. Gadzekpo,’ James M. Hungerford, Azza M. Kadry,* Yehia A. Ibrahim,3 and Gary D. Christian* Department of Chemistry BG-10, University of Washington, Seattle, Washington 98195 A lithium ion selective electrode was constructed with N,N’-diheptyi-5,5-dimethyi-N,N’-bis( 3-oxapentyi)-3,7-dioxa- nonanediamide as a lithium carrier. Dioctyi azeiaie, tris( 2- ethyihexyi) phosphate, and triisononyi trimelitate were used as plasticizers. Selectivity coefficients of 0.063, 0.104, 7.1 X and 2.5 X are reported for sodium, potassium, calcium, and magnesium, respectively, relative to lithium ion. A new and simpler procedure is reported for the synthesis of the lithium carrier. Lithium carriers are very important in lithium transport through the blood brain barrier and across other membranes (1-3). Shanzer et al. ( 4 ) reported the transport properties of N,Nr-diheptyl-5,5-dimethyl-N,N’-bis( 3-oxapentyl)-3,7-dioxa- nonanediamide (Figure 1). This tetroxadiamide is reported to be an efficient carrier for lithium ion. It is said to wrap around the lithium ion in an octahedral arrangement using six binding sites and is reported to carry lithium ions as ef- ficiently as valinomycin carries potassium ions, possibly for structural reasons. The carrier selectivity of the tetroxadi- amide for lithium ion estimated by equilibrium partition experiments performed in a water/methylene chloride system with lithium chloride and sodium chloride gave values of more than 40 ( 4 ) . The reported efficient transporting capability of the tetroxadiamide has led us to investigate its characteristic behavior as a carrier in a lithium ion selective electrode. Present address: Department of Applied Chemistry, The Univ- ersity of Wales Science and Technology, P.O. Box 13, Cardiff CF1 3x1, United Kingdom. *On leave from Department of Chemistry, Faculty of Pharmacy, Za azig University, Zagazig, Egypt. !Fulbright Scholar, on leave from Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt. Several acyclic polyethers (5), macrocyclic crown ethers (6, 7), and acyclic dioxadiamides (8-10) have been investigated as carriers in lithium ion selective electrodes. Selectivities reported for most of these neutral carriers in ion-selective electrodes for lithium over other cations, however, are not high enough to enable them to be used in most lithium determi- nations. EXPERIMENTAL SECTION Synthesis of Lithium Carrier [N,N’-Diethyl-5,5-di- methyl-N~-bis(3-oxapentyl)-3,7-dioxanonanediamine] ( 1). The synthesis (Figure 2) of compound 1, described recently by Shanzer et al. ( 4 ) , is based on the use of the cyclic stannoxane (3), prepared by reacting 2,2-dimethyl-1,3-propanediol (2) with dibutyltin diethoxide. Subsequent reaction of 3 with N- heptylbromoacetamide was described to give N,N’-diheptyl-5,5- dimethyl-3,7-dioxanonanediamide (4) which was then alkylated with 2-bromoethyl ethyl ether to yield 1 ( 4 ) . Attempts to repeat the above synthesis of the intermediate 4 showed the complexity of the reaction product, which needed a tedious chromatographic separation (11). We have investigated two alternative and simpler routes toward the synthesis of the tetraoxadiamide 1. Thus, treatment of the diol 2 with ethyl diazoacetate gave the ester 5 (12). Reaction of the ester 5 with n-heptylamine cleanly yielded the amide (4) in an almost quantitative yield. Amide 4 was then converted into the desired ionophore 1 following the same pro- cedure described by Shanzer et al. ( 4 ) . More direct and efficient synthesis of 1 has been achieved by reacting the acid chloride 7 with N-(2-oxapentyl)heptylamine (10). The acid chloride (7) was obtained from ester 5 by hydrolysis to the corresponding acid (6) followed by reaction with thionyl chloride. N-(3-Oxapentyl)heptylamine (10) used in this inves- tigation was readily obtained by lithium aluminum hydride re- duction of N-heptylethoxyacetamide (9). The latter compound was synthesized by the condensation of ethyl ethoxyacetate (8) with n-heptylamine. a. N,N’-Diheptyl-5,5-dimethyl-3,7-dioxanonanediamide (4). A mixture of ester 5 (5.52 g, 0.02 mol) and n-heptylamine 0003-2700/85/0357-0493$01.50/0 e 1985 American Chemical Society 494 ANALYTICAL CHEMISTRY, VOL. 57, NO. 2, FEBRUARY 1985 Figure 1. Structure of lithium ion carrier. 6, X:OH 7, X = C I C ~ H S O C H ~ C O & ~ H S t C7Y,", - C~HSOCH~CONHC+IIS 8 9 Figure 2. Synthesis scheme for lithium ion carrier (1). was heated under reflux for 5 h. After cooling, the reaction mixture was diluted with ether (100 mL) and washed twice with hydrochloric acid (20 mL, 5 N), followed by water, saturated sodium bicarbonate, and then water again. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the diamide 4 as an oil, 8.1 g (ca. 97%). Compound 4 obtained by this procedure is identical in all respects with the reported data (NMR and IR) (4) and was used in the subsequent step without further purification. b. N-Heptylethoxyacetamide (9). A mixture of ethyl eth- oxyacetate (8) (6.6 g, 0.05 mol) and N-heptylamine (5.75 g, 0.05 mol) was heated under reflux for 10 h. After cooling, the reaction mixture was diluted with ether (100 mL) and worked up exactly as in the synthesis of the diamide 4. Compound 9 was obtained as an oil, 9.1 g (ca. 91%): NMR (CDClJ 6 7.02 (br, 1 H, NH), and 0.78-1.6 (m, 15 H, aliphatic hydrogens) ppm; IR (neat) 1665 cm-' (amide CO). c. N-(3-Oxapentyl)heptylamine (10). To a solution of 9 (6.8 g, 0.034 mol) in anhydrous ether (50 mL) was added lithium aluminum hydride (4.5 g) portionwise with cooling and stirring, followed by anhydrous benzene (20 mL). The reaction mixture was heated under reflux for 15 h. After the reaction mixture was cooled, water (15 mL) was added dropwise, with stirring and cooling, followed by sodium hydroxide (10 mL, 15% w/v). The organic layer was then separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give compound 10 as a yellow oil, 6.2 g (ca. 98%): bp 235-240 "C; NMR (neat) 6 3.1-3.5 (m, 4 H, CH20CH2), 2.2-2.6 (m, 5 H, CH2NHCH2), and 0.7-1.5 (m, 15 H, aliphatic hydrogens) ppm; IR (neat) 3300-3100 (br), 2950,2920,2850,1450,1395,1380,1115,1105 cm-'. d. N,N'-Diheptyl-5,5-dimethyl-N,N'-bis(3-oxapentyl)- 3,7-dioxanonanediamide (1). A solution of the acid chloride 7 (12) (1.0 g, 0.0039 mol) in benzene (10 mL) was added dropwise with stirring and cooling (ice bath) to a solution of the amine 10 (1.56 g, 0.0083 mol) in methylene chloride (15 mL) and tri- ethylamine (3 mL). After the addition was complete, the reaction mixture was left at room temperature overnight and then methylene chloride (50 mL) was added. The solution was washed 3.85 (9, 2 H, OCHZCO), 3.6 (q, 2 H, CHZO), 3.22 (t, 2 H, NCHZ) Table I. Selectivity Coefficients (e;&) for Electrodes KPOt interferent Li,M ion, M membrane 1 membrane 2 membrane 3 Na+ 0.063 0.065 0.085 K+ 0.10 0.070 Ca2+ 7.1 x 10-3 9.2 x 10-3 Mg2+ 2.5 x 10-4 2.1 x 10-3 twice with distilled water, twice with hydrochloric acid (20 mL, 5 N), twice with water, saturated sodium bicarbonate solution, and finally with water. The organic layer was dried over an- hydrous sodium sulfate and concentrated in vacuo to give product 1 as a yellow oil, 1.8 g (ca. 82%). This was purified by column chromatography using silica gel, eluting first with petroleum ether (30-60, 100 mL), followed by a mixture of petroleum ether (30-60 "C) and chloroform (2:l). The yield was 1.5 g (68%). The IR, NMR, and mass spectra of the product were identical with the reported values (4). Reagents and Chemicals. High molecular weight poly(viny1 chloride) (PVC) was obtained from Fluka AG. Dioctyl azelate was obtained from Polysciences and tris(2-ethylhexyl) phosphate was obtained from U.C.C Flexoh. All solutions were prepared from salts of reagent grade using dionized water. The chlorides of the metals were used in all cases. Electrode System. Measurements were performed by use of the following cell: Hg;HgzC12,KCl(satd) Ilsample solutionlmembranelAgC1;Ag A Beckman digital pH meter (Model 4500) was used in mon- itoring the voltage. a. PVC-Plasticizer Stock Solution (13). Poly(viny1 chlo- ride) (0.6 g) was mixed with 1.36 g of plasticizer. The mixture was stirred while all the PVC was wet. Cyclohexanone (7.5 mL) was next added to the mixture and the mixture was shaken until all the PVC dissolved. b. Electrode Fabrication. Two aliquots of 25 ,uL of PVC- plasticizer-lithium carrier solution were carefully deposited on a compact silver-silver chloride plug of a Beckman threaded ion selective electrode tip. The second aliquot was deposited after the first aliquot had almost evaporated. The tip was left to stand for 24 h. It was soaked in 0.1 M LiCl solution for 24 h before use. Membrane Preparation. a. Membrane 1. The lithium carrier (2.7 mg) was added to 250 ,uL of stock PVC solution containing tris(2-ethylhexyl) phosphate as plasticizer. The electrode was fabricated as indicated above. b. Membrane 2. Lithium carrier (5.7 mg) was added to 250 pL of stock PVC solution containing dioctyl azelate as plasticizer. The electrode was fabricated as indicated above. c. Membrane 3. Lithium carrier (15.8 mg) was mixed with 250 pL of stock PVC solution containing triisononyl trimelitate as plasticizer. The electrode was fabricated as indicated above. Selectivity Coefficients (KLi,M). Selectivity coefficients for the different membranes were determined by the mixed solution method (14-16). For membrane 1, they were also determined by the separate solution method (I 7) and the matched-potential method (18). In the latter, the electrode is immersed in a 1 mM lithium ion reference solution and the potential change is recorded upon increasing the lithium concentration an additional 1 mM. Then the secondary ion (e.g., sodium) is added in increments to an identical reference solution until the same potential change occurs. The ratio of concentrations of primary ion to secondary ion required to give the same potential change in the reference solution represents the selectivity coefficient. RESULTS AND DISCUSSION Linear response was obtained for the electrode containing membrane 1 with a linear slope of 53 mV/decade. The electrode response was quite fast and equilibrated within a few seconds. In order for the electrode to be used in lithium analysis in blood serum of manic depressive patients, it must have a high selectivity for lithium ion over sodium since the amount of sodium in the blood is about 140 times more than lithium. Selectivities determined for the electrodes in this Table 11. Selectivity Coefficient (K&) for Electrode with Membrane 1 inteferent separate solution matched-potential ion method method Na+ 0.051 0.047 * 0.005" K+ 5.3 x 10-3 Ca2+ 3.6 x 10-3 Mg2+ 4.0 x 10-4 "Standard deviation, n = 3. mV 80 60 4 0 2 0 n - 4 - 3 - 2 - 1 Log [ ~ i + ] Figure 3. Response of electrode (membrane 1) in 140 mM NaCl solution. study are summarized in Tables I and 11. The electrode with membrane 1 is about 16 (Table I) to 21 (Table 11) times more selective for lithium than for sodium and 10 (Table I) to 190 (Table 11) times more selective for lithium than for potassium. This compares with a selectivity of 8 using 12-crown-4 ionophore (13) and about 100 for the dioxadimide reported by Zhukov e t al. (10). The selectivity, particularly for lithium over sodium, is not high enough to enable the electrode to be used for direct lithium analysis in blood. Even though the electrode could sense lithium in 140 mM sodium solution (Figure 3), the change in potential a t the lithium concentration of interest will be small and in the nonlinear region of the curve, and so very careful calibration would be required. Some plasticizers do enhance the selectivity of carriers in membranes, since the mobility of the carrier is dependent on the plasticizer. We, therefore, investigated the behavior of the lithium carrier in membranes with different plasticizers. For the electrode containing membrane 2 and membrane 3, a linear response was obtained with a slope of 54 and 45 ANALYTICAL CHEMISTRY, VOL. 57, NO. 2, FEBRUARY 1985 495 mV/decade, respectively. The response time and equilibration time were slightly slower than those observed for the electrode containing membrane 1. The electrode containing membrane 2 gave a selectivity of 15.5 for lithium over sodium while the electrode containing membrane 3 gave a corresponding se- lectivity of 11.7. The selectivity values of the three types of electrodes are very comparable. This indicates that the plasticizers used in this case do not enhance the selectivity significantly from one to another. The effect of temperature on selectivity was investigated by using the mixed solution method. At 41 "C a linear slope of 63 mV/decade was obtained for the electrode with mem- brane 1. A selectivity coefficient for sodium relative to lithium of 0.053 was obtained. At 80 "C, however, the electrode be- came very noisy and no meaningful results were obtained. ACKNOWLEDGMENT We acknowledge the technical assistance of David Fried- Registry No. 1, 80712-94-3; 2, 126-30-7; 3, 592-55-2; 4, 9, 93404-40-1; 10, 93404-41-2; dioctyl azelate, 103-24-2; tris(2- ethylhexyl)phosphate, 78-42-2; triisononyl trimelitate, 53894-23-8; lithium, 7439-93-2. man. 85553-29-3; 5,65115-08-4; 6,65115-11-9; 7,65115-09-5; 8,817-95-8; LITERATURE CITED Samuel, D.; Gottesfeld, 2. Endeavour 1973. 32, 122-128. Johnson, F. N., Ed. "Lithium Research Therapy"; Academic Press: London, 1975; pp 267-280. Johnson, F. N. Neurosci. Blobehav. Rev. 1979? 3 , 15. 375. Shanzer, A.; Samuel, D.; Korenstein, R. J. Am. Chem. SOC. 1983, 105, 3815-3818. Hiratani, K. Chem. Lett. 1982, 1021-1024. Olsher, U.; Jagur-Grcdzinski, J. J. Chem. Soc., Dalton Trans. 1981, Aalmo, K. M.; Krane, J. Acta Chem. Scand., Ser. A 1982, 3 6 , Simon, W.; Pretsch, E.; Ammann, D.; Morf, W. E.; Guggi, M.; Bissing, R.; Kessler, M. Pure Appl. Chem. 1975, 4 4 , 613-626. Bissing. R.; Pretsch, E.; Morf, W. E.; Simon, W. Helv. Chim. Acta 1978. 6 1 , 1520-1530. Zhukov. A. F.; Erne, D.; Amman, D.; Guggi, M.; Pretch, E.; Simon, W. Anal. Chim. Acta 1981, 131, 117-122. Hawkins, J. J., Beckman Instruments, Inc., private communication. Kirsch, N. L.; Funck, R. J. J.; Prettsch, E.; Simon W. Helv. Chim. Acta 501-505. 227-234. 1977, 6 0 , 2326-2333. Gadzekpo, V. P. Y.; Christian, G. D. Anal. Lett. 1983, 16, 1371-13ai. Wilson, M. F.: Haikala, E.; Kivalo. P. Anal. Chim. Acta 1975, 74 , 395-410. Bailey, P. L. "Analysts wlth Ion-Selective Electrodes", 2nd ed.; Hey- den: London, 1980; pp 46-50. IUPAC Pure Appl. Chem. 1976, 48, 127-132. Srinvasan, K.; Rechnitz, G. A. Anal. Chem. 1969, 41 , 1203-1208. Gadzekpo, V . P. Y.; Christian, G. D. Anal. Chlm. Acta, in press. RECEIVED for review August 16, 1984. Accepted October 26, 1984. The Fulbright Fellowship to Y. A. Ibrahim is gratefully acknowledged. This work was supported in part by Beckman Instruments, Inc.