Design and synthesis of sodium ion-selective ionophores based on 16-crown-5 derivatives for an ion-selective electrode

Article abstract of DOI:10.1021/ac950773j

To develop an ionophore that is highly selective for sodium for use in an ion-selective electrode, we propose a model based on 16-crown-5 which has a cavity just the size of Na⁺ and has a "block" subunit to prevent complex formation with ions l

Full text of DOI:10.1021/ac950773j

Anal. Chem. 1996, 68, 208-215
Design and Synthesis of Sodium Ion-Selective
Ionophores Based on 16-Crown-5 Derivatives for an
Ion-Selective Electrode
Koji Suzuki,* Kazunari Sato, Hideaki Hisamoto, Dwi Siswanta, Kazuo Hayashi, Noriko Kasahara,
Kazuhiko Watanabe, Noriko Yamamoto, and Hideshi Sasakura
Department of Applied Chemistry, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223, Japan
zyl ether, for which the Na+/ K+ selectivity was ∼600.3 Unfortu-
To develop an ionophore that is highly selective for
nately, the lifetime of this electrode is not good because of the
low lipophilicity of the 16-crown-5 derivative (log Po/ w ) 3.4 (
0.3).
sodium for use in an ion-selective electrode, we propose
a model based on 1 6 -crown-5 which has a cavity just the
size of Na+ and has a “block” subunit to prevent complex
formation with ions larger than Na+. Based on this
molecular model, eight kinds of 1 6 -crown-5 derivatives
have been synthesized, and their structural ion selectivity
has been evaluated in detail. The 1 6 -crown-5 derivatives
having two bulky “block” subunits showed high Na+
selectivity relative to K+. In particular, the derivative with
two decalino subunits (DD1 6 C5 ) exhibited the highest
Na+ selectivity of all the ionophores examined. When a
phosphate ester-type membrane plasticizer, tris(ethyl-
hexyl) phosphate, was used as the membrane solvent for
the ion-sensing membrane based on poly(vinyl chloride),
the electrode using DD1 6 C5 exhibited a Na+ selectivity
of over 1 0 0 0 times relative to alkali metal and alkaline
earth metal ions, including K+, which is the most serious
interferant. The evaluation of the relationship between
the ionophore chemical structures and the ion-selective
features contributes to the host-guest chemistry to give
a highly selective ionophore for an alkali metal ion.
Generally, a crown ether forms an 1:1 complex with a metal
cation that has an ionic size fitting the cavity size of the crown
ether ring, but most of the crown ether compounds also often
form a sandwich-type complex with a large cation (a 1:2 or 1:3
ion-ligand complex), because crown ether compounds have a
relatively planar and flexible structure, except when the compound
has a small ring size. To prevent the formation of a sandwich-
type complex, introduction of a bulky blocking wall (a block
subunit) into the crown ether (as the shown in Figure 1) is very
effective for improving the selectivity as well as the lipophilicity.
Cations larger than Na+ cannot be positioned within an appropriate
binding distance of the oxygen atom (the cation binding site in
the crown ether ring) due to the presence of the block subunit,
as illustrated in Figure 1. Thus, a stable sandwich-type complex
with a large cation cannot be formed (block effect). Consequently,
a higher selectivity for the cation that fits in the cavity of the crown
ether ring can be obtained. We have applied this approach in
the design and synthesis of a highly Li+ selective ionophore and
have successfully obtained an ionophore which has a Li+ selectivity
of over 1000 times relative to all other alkali metal and alkaline
earth metal ions.5
To add an effective block subunit in the crown compound, the
following points must be considered: (i) the bulky subunit has
to be positioned in the crown compound such that its large
physical bulk is oriented in an up-and-down position relative to
the crown ring; (ii) in this case, the bulky subunit should be able
to support the rigidity of the crown ring so that the ring size is
fixed; and (iii) the block subunit is positioned near the oxygen
donor atom in the crown ether compound so that the appropriate
space for the larger coordinating cation (interfering ion) to bind
to the oxygen atom is not offered.
Sodium ion is an important chemical species in the metabolism
processes of the human body; therefore, measurement of the
concentration of sodium ions is useful in controlling human health
conditions and diagnosing sicknesses. Recently, Na+-selective
electrodes have been used in hospitals for routine clinical
measurement of Na+ concentration. Using this sensor, an analyti-
cal instrument that can rapidly and easily measure the Na+
concentration in human serum has been constructed. Sodium
ion concentration in normal human serum (extracellular fluid) is
The number of block subunits in the crown ether compound
is an important factor as well. Generally, we simply expect that
a larger number of block subunits causes a greater block effect.
However, if too many block subunits are introduced in the crown
ether compounds, the bulky block walls sterically interfere with
even the cation having a suitable size to fit the cavity of the crown
ring. Thus, the optimum number and suitable type of bulky block
subunits have to be introduced in the crown ether.
Based on the model shown in Figure 1, we designed and
synthesized eight kinds of novel 16-crown-5 derivatives and
evaluated their structural selectivity. 16-Crown-5 derivatives
having two block subunits exhibited a very high Na+ selectivity,
∼140 mM, which is a relatively high concentration; thus, an ion-
pot
selective electrode having a selectivity coefficient of log
k
Na,K
<-0.6 is adequate for this measurement.1 As for intracellular
fluid, the Na+ concentration is small compared with that of the
coexisting K+ (Na+, ∼10 mM; K+, 120 mM). The required Na+/
K
+ selectivity is 4000 in the case where the Na+ determination is
performed with an ion-selective electrode in which the measure-
ment error is assumed to be <1%.1 Thus, a very highly Na+
selective electrode is desired for this measurement. Furthermore,
in order to construct a long-lifetime and highly reproducible ion-
selective electrode, a high lipophililicity value of log Po/ w >11.3 is
required for the ionophore as one of the ion-sensing electrode
membrane components when the electrode is used in the analysis
of human serum.2 In the past, we have obtained a highly Na+-
selective electrode based on a 16-crown-5 derivative [15-(benzyl-
oxy)methyl-15-ethyl-1,4,7,10,13-pentaoxacyclohexadecane] and diben-
(2) Dinten, O.; Spichger, U. E.; Chaniotokis, N.; Gehrig, P.; Rusterholz, B.; Morf,
W. E.; Simon, W. Anal. Chem. 1 9 9 1 , 63, 596.
(3) Suzuki, K.; Hayashi, K.; Tohda, K.; Watanabe, K.; Ouchi, M.; Hakushi, T.;
Inoue, Y. Anal. Lett. 1 9 9 1 , 24, 1085.
(4) Pearson, R. G. J. Chem. Educ. 1 9 6 8 , 45, 643.
(1) Ammann, D. Ion-Selective Microelectrodes; Springer-Verlag: New York, 1986;
(5) Suzuki, K.; Yamada, H.; Sato, K.; Watanabe, K.; Hisamoto, H.; Tobe, Y.;
Kobiro, K. Anal. Chem. 1 9 9 3 , 65, 3404.
Chapter 7.
208 Analytical Chemistry, Vol. 68, No. 1, January 1, 1996
0003-2700/96/0368-0208$12.00/0 © 1995 American Chemical Society

NaH (2.88 g, 72.0 mmol) was gradually added to a solution of
1 (10.0 g, 48.0 mmol) in 200 mL of THF and stirred for 50 min.
A solution of allyl bromide (8.72 g, 72 mmol) in 90 mL of THF
was then added and stirred at 50 °C for 20 h. A small amount of
methanol was added to quench the excess NaH. After evaporation
of THF, the residue was extracted three times with ethyl acetate.
The ethyl acetate was evaporated and the obtained residue purified
by silica gel column chromatography with hexane-ethyl acetate
(9:1) as the eluent to yield 6-(benzyloxy)-5,5,6,-trimethyl-4-oxa-
heptene (2 ; 8.37 g, 70.22%) as a colorless oil.
Product 2 (8.37 g, 33.7 mmol) was added to a solution of
sodium borohydride (NaBH4) in 20 mL of THF. While the
mixture was being stirred in an ice bath, a solution of boron
trifluoride etherate complex [BF3(C2H5)2O; 2.87 g, 20.2 mmol] in
30 mL of THF was added gradually over 1 h. After 2 was
consumed (determined by TLC), 3 M NaOH (0.54 g, 13.48 mmol)
was added, followed by the 30% H2O2 (4.6 mL, 40.4 mmol). The
reaction mixture was stirred for 3 h. The reaction product was
then extracted three times with ethyl acetate and the obtained
residue purified by a silica gel column chromatography with
hexane-ethyl acetate (6:1) as the eluent to yield 6-(benzyloxy)-
5,5,6-trimethyl-4-oxaheptanol (3 ; 4.92 g, 54.8%) as a colorless oil.
A solution of 3 (3.63 g, 13.6 mmol) in 15 mL of methanol was
added to a suspension of 7.5 wt % Pd-C (1.8 g, 50 wt %) in 20 mL
of methanol. The methanol mixture was stirred at room temper-
ature under 1 atm H2 for 22 h. After the solid was filtered off, the
liquid was evaporated to yield 2,3,3-trimethyl-4-oxa-2,7-heptanediol
(4 ; 2.00 g, 83.4%). NaH (1.35 g, 33.7 mmol) was added to a
solution of pinacol (1.66 g, 14.1 mmol) in THF (50 mL) and stirred
for 30 min. A solution of benzyl bromide (7.77 g, 33.7 mmol) in
75 mL of THF was added gradually to this mixture. The mixture
was then stirred at 60 °C for 5 days. A small amount of methanol
was added to quench the excess NaH. After evaporation of THF,
the residue was extracted three times with ethyl acetate. The
solvent was then evaporated and the obtained residue purified
by silica gel column chromatography with hexane-ethyl acetate
(4:1) as the eluent to yield 1,8-bis(benzyloxy)-4,4,5,5-tetramethyl-
3,6-dioxaoctane (5 ; 337.6 mg, 6.22%) as a colorless oil.
Figure 1. Na+-selective ionophore model molecules based on 16-
crown-5 with and without bulky block subunits. i, primary ion (Na+);
j, interfering ion (K+).
especially the derivative with two decalino subunits (DD16C5),
which exhibited the highest Na+ selectivity. The ion-selective
electrode based on DD16C5 exhibited 1000 times the Na+
selectivity relative to that for K+ and over 1000 times relative to
that for other alkali metal and alkaline earth ions when a
phosphate ester-type membrane solvent, TEHP, was used as
membrane solvent in the polymeric electrode membrane based
on PVC. DD16C5 satisfies the requirement for a long-lifetime and
highly reproducible ion-selective electrode of adequate lipophilicity
(log Po/ w ) 11.8); therefore, it is an excellent ionophore for Na+
for application as a membrane component of the Na+-selective
electrodes developed to date.
A solution of product 5 (842.3 mg, 2.18 mmol) in 10 mL of
methanol was added to a suspension of 7.5 wt % Pd-C (420 mg,
50 wt %) in 4 mL of methanol. The mixture was stirred at room
temperature under 1 atm H2 for 20 h. After the solid was filtered
off, the mixture was evaporated to yield 4,4,5,5- tetramethyl-3,6-
dioxa-1,8-octanediol (6 ; 2.00 g, 59.6%).
EXPERIMENTAL SECTION
Tosyl chloride (544.5 mg, 2.86 mmol) was added to a solution
of 6 (267.8 mg, 1.30 mmol) in 3 mL of pyridine and stirred for 3
h in an ice bath. The reaction mixture was evaporated and the
residue extracted three times with ethyl acetate. The solvent was
collected and evaporated. The obtained residue was purified by
silica gel column chromatography with hexane-ethyl acetate (2:
1) as the eluent to yield 4,4,5,5-tetramethyl-3,6-dioxa-1,8-octanediol
ditosylate (7 ; 314.6 mg, 47.1%) as a white solid.
NaH (97.8 mg, 2.45 mmol) was added to a solution of 4 (107.7
mg, 0.61 mmol) in THF (3 mL) and stirred for 30 min. A solution
of 7 (314.6 g, 0.6 mmol) in 5 mL of THF was then added to this
mixture and stirred at 70 °C for 22 h. A small amount of methanol
was added to quench the excess NaH. After evaporation of THF,
the residue was extracted three times with ethyl acetate. The
ethyl acetate was then evaporated and the obtained residue
purified by silica gel column chromatography with hexane-ethyl
acetate (1:1) as the eluent to yield 2,2,3,3,8,8,9,9-octamethyl-1,4,7,
10,13-pentaoxacyclohexadecane (DTM16C5A; 18.4 mg, 8.69%) as
a colorless oil. Analytical data for DTM16C5A are as follows: 1H-
NMR (90 MHz, CDCl3) δ 1.20 (s, 24H, 8 -CH3), 1.75 (m, 2H,
-CH2CH2CH2), 3.30-3.80 (m, 12H, -OCH2-). Anal. Calcd for
C19H38O5 (346.51): C, 65.86; H, 11.05. Found: C, 65.89; H, 11.01.
(ii) DTM16C5B (2,2,3,3,11,11,12,12-Octamethyl-1,4,7,
1 0 ,1 3 -pentaoxacyclohexadecane). To a solution of pinacol
Reagents. The highest grade commercially available reagents
were used for syntheses of the new compounds and preparation
of the aqueous test electrolytes. The distilled and deionized water
used had a resistivity of 1.5 × 107 Ω cm at 25 °C. The electrode
membrane solvent bis(1-butylpentyl) adipate (BBPA) was pur-
chased 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 1 6 -Crown-5 Derivatives. The procedures for
the preparation of new ionophores as follows:
(i) DTM1 6 C5 A (2 ,2 ,3 ,3 ,8 ,8 ,9 ,9 -Octamethyl-1 ,4 ,7 ,1 0 ,
1 3 -pentaoxacyclohexadecane). Sodium hydride (NaH; 2.56 g,
64.0 mmol) was added to a solution of pinacol (6.30 g, 53.3 mmol)
in tetrahydrofuran (THF; 130 mL) and stirred for 30 min at room
temperature. A solution of benzyl bromide (8.21 g, 48 mmol) in
60 mL of THF was added gradually to this mixture and was then
stirred at 80 °C for 20 h. A small amount of methanol was added
to quench the excess NaH. After evaporation of THF, the residue
was extracted three times with ethyl acetate. The solvent was
then evaporated and the obtained residue purified by silica gel
column chromatography with hexane-ethyl acetate (9:1) as the
eluent to yield 3-(benzyloxy)-2,3-dimethyl-2-butanol (1 ; 7.01 g,
71.0%) as a colorless oil.
Analytical Chemistry, Vol. 68, No. 1, January 1, 1996 209

(7.27 g, 61.5 mmol) and malonaldehyde bis(dimethyl acetal) (5.0
g, 30.45 mmol) in benzene (150 mL) was added a catalytic amount
of p-toluenesulfonic acid monohydrate (100 mg), and the mixture
was stirred at 90 °C for 2 h. The reaction mixture was then
evaporated and partitioned three times with chloroform. The
chloroform was then evaporated and the residue purified by silica
gel column chromatography with hexane-ethyl acetate (4:1) as
the eluent to yield 2,2′-methylenedi-4,4,5,5-tetramethyl-1,3-diox-
olane (8 ; 7.87 g, 95.0%) as white crystals.
the residue was extracted three times with ethyl acetate. The
organic solvent was then evaporated, and the obtained residue
was purified by HPLC with acetone as the eluent to yield 2,6,13,
16,19-pentaoxapentacyclo[18.4.4.47,12.01,20.07,12]dotriacontane
(DD16C5; 68.5 mg, 15.2%) as a colorless oil. Analytical data for
DD16C5 are as follows: 1H-NMR (90 MHz, CDCl3) δ 1.10-2.35
(m, 34H, -CH2-), 3.25-4.00 (m, 12H, -OCH2-). Anal. Calcd
for C27H46O5 (450.67): C, 71.96; H, 10.29. Found: C, 72.01; H,
10.33.
A solution of lithium aluminum hydride (752 mg, 19.8 mmol)
in 10 mL of ether was added to a solution of aluminum chloride
(10.57 g, 79.3 mmol) in 130 mL of ether and stirred in a water
bath for 30 min. Product 8 (3.0 g, 11 mmol) was then added and
the solution stirred for 3 h. After the addition of water (25 mL),
followed by addition of 10% H2SO4 solution (25 mL), the organic
layer was decanted and the water phase extracted three times
with ethyl acetate. The organic solvent was then collected and
evaporated, and the obtained residue was purified by silica gel
column chromatography with hexane-ethyl acetate (1:1) as eluent
to yield 2,3,3,9,9,10-hexamethyl-4,8-dioxa-2,10-undecanediol (9 ;
2.46 g, 80.9%) as a white solid.
NaH (290 mg, 7.2 mmol) was added to a solution of 9 (500
mg, 1.8 mmol) in THF (10 mL) and stirred at 40 °C for 1 h. A
solution of diethylene glycol dimesylate (474.3 g, 1.8 mmol) in 10
mL of THF was then added to this mixture. The mixture was
then stirred at 70 °C for 20 h, and a small amount of methanol
was added to quench the excess NaH. After evaporation of THF,
the residue was extracted three times with ethyl acetate. The
organic solvent was then evaporated and the obtained residue
purified by silica gel column chromatography with hexane-ethyl
acetate (1:4) as the eluent to yield 2,2,3,3,11,11,12,12-octamethyl-
1,4,7,10,13-pentaoxacyclohexadecane (DTM16C5B; 23.4 mg, 3.7%)
as a colorless oil. Analytical data for DTM16C5B are as follows:
1H NMR (90 MHz, CDCl3) δ 1.16 and 1.20 (s, 24H, 8 -CH3), 1.72
(m, 2H, -CH2CH2CH2), 3.54-3.68 (m, 12H, -OCH2-). Anal.
Calcd for C19H38O5 (346.51): C, 65.86; H, 11.05. Found: C, 66.01;
H, 11.07.
(iii) DD1 6 C5 (2 ,6 ,1 3 ,1 6 ,1 9 -P entaoxapentacyclo[1 8 .4 .
4 .4 7 ,1 2 .0 1 ,2 0 .0 7 ,1 2 ]dotriacontane). To a solution of cis-1,6-
dihydroxybicyclo[4.4.0]decane (4.19 g, 24.6 mmol) and malonal-
dehyde bis(dimethyl acetal) (2.0 g, 12.2 mmol) in benzene (60
mL) was added a small amount of p-toluenesulfonic acid mono-
hydrate (400 mg), and the solution was stirred at 90 °C for 2 h.
The reaction mixture was evaporated and partitioned three times
with chloroform. The organic solvent was then evaporated. The
residue was dissolved in a small amount of chloroform (20 mL),
and then methanol (20 mL) was added and the mixture cooled at
0 °C for 2 h. The resulting white crystals were filtered out and
identified as 12,12′-methylenedi-11,13-dioxatricyclo[4.4.3.01.6]tridecane
(1 0 : 2.35 g, 51.4%).
A solution of lithium aluminum hydride (436 mg, 11.47 mmol)
in 10 mL of ether was added to a solution of aluminum chloride
(6.12 g, 45.89 mmol) in 130 mL of ether and stirred in a water
bath for 30 min. Product 1 0 (2.4 g, 6.37 mmol) was then added
and the solution stirred for 3 h. After the addition of water (25
mL), followed by addition of 10% H2SO4 solution (25 mL), the
solvent was decanted and the water phase 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) as eluent to yield 6,6′-(propyl-
enedioxy)di-cis-1-hydroxydecane (1 1 ; 821.1 mg, 33.8%) as a white
solid.
(iv) C1 4 -DTM1 6 C5 B (2 ,2 ,3 ,3 ,1 1 ,1 1 ,1 2 ,1 2 -Octamethyl-
6 -tetradecyl-1 ,4 ,7 ,1 0 ,1 3 -pentaoxacyclohexadecane). Trityl
chloride (7.62 g, 27.3 mmol) was added to a solution of 1,2-
hexadecanediol (7.0 mg, 27.08 mmol) in 300 mL of pyridine and
stirred at 60 °C for 12 h. The reaction mixture was then
evaporated, and the residue 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 (6:1) as the eluent to yield 1-trityloxyhexa-
decan-2-ol (1 2 ; 10.0 g, 73.8%) as a white solid.
Mesyl chloride (7.90 g, 68.99 mmol) was added to a solution
of (benzyloxy)ethanol (10 g, 65.7 mmol) in 60 mL of pyridine and
stirred for 30 min in an ice bath. The reaction mixture was then
evaporated, and the residue was extracted three times with ethyl
acetate. The solvent was collected and evaporated. The obtained
residue was purified by silica gel column chromatography with
hexane-ethyl acetate (2:1) as the eluent to yield 2-(benzyloxy)-
ethanol mesylate (1 3 ; 12.4 mg, 82.1%) as a colorless oil.
To a solution of product 1 2 (5.3 g, 10.58 mmol) in THF (60
mL) was added NaH (508 mg, 12.7 mmol), and the mixture was
stirred at 40 °C for 1 h. A solution of 1 3 (2.68 g, 11.6 mmol) in
20 mL of THF was added to this mixture. The mixture was then
stirred at 70 °C for 20 h. A small amount of methanol (20 mL)
was added to quench the excess NaH. After evaporation of THF,
the residue was extracted three times with ethyl acetate. The
organic solvent was then evaporated, and the obtained residue
was purified by silica gel column chromatography with hexane-
ethyl acetate (19:1) as the eluent to yield 5-(benzyloxy)-2-
tetradecyl-1-(trityloxy)-3-oxapentane (1 4 ; 4.05 g, 60.2%) as a
colorless oil.
Product 1 4 was dissolved in mixture of THF-H2O-AcOH (4:
1:7 v/ v/ v; 120 mL) and stirred at 60 °C for 4 h. After evaporation
of the solvent, the residue was extracted three times with ethyl
acetate. Then organic solvent was then evaporated, and the
obtained residue was purified by silica gel column chromatography
with hexane-ethyl acetate (6:1) as the eluent to yield 5(benzyl-
oxy)-2-tetradecyl-3-oxapentan-1-ol (15; 4.88 g, 69.3%) as a colorless
oil.
A solution of 1 5 (5.72 g, 14.56 mmol) in 30 mL of ethanol was
added to a suspension of 7.5 wt % Pd-C (2.8 g, 50 wt %) in 30 mL
of ethanol. The reaction mixture was then stirred at room
temperature under 1 atm H2 for 20 h. After the solid was filtered
off, the mixture was evaporated to yield 2-tetradecyl-3-oxa-1,5-
pentanediol (1 6 ; 4.21 g, 95.4%) as a colorless oil.
Mesyl chloride (3.34 g, 29.16 mmol) was added to a solution
of 1 6 (4.20 g, 13.88 mmol) in 40 mL of pyridine and stirred for
30 min in an ice bath. The reaction mixture was then evaporated,
and the residue 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 (1:1) as the eluent to yield 2-tetradecyl-3-oxa-1,5-pen-
tanediol dimesylate (1 7 ; 4.81 g, 75.5%) as a colorless oil.
NaH (290 mg, 7.2 mmol) was added to a solution of 9 (500
mg, 1.8 mmol) in THF (15 mL) and stirred at 40 °C for 1 h. A
solution of 1 7 (830 mg, 1.8 mmol) in 12 mL of THF was then
added to this mixture. The mixture was then stirred at 70 °C for
20 h. A small amount of methanol was added to quench the
excess NaH. After evaporation of THF, the residue was extracted
three times with ethyl acetate. The solvent was then evaporated,
NaH (250 mg, 6.25 mmol) was added to a solution of 1 1 (380.4
mg, 1.0 mmol) in THF (8 mL) and stirred at 40 °C for 1 h. A
solution of diethylene glycol dimesylate (262.1 g, 1.0 mmol) in 6
mL of THF was added to this mixture. The mixture was then
stirred at 70 °C for 20 h. A small amount of methanol (20 mL)
was added to quench the excess NaH. After evaporation of THF,
210 Analytical Chemistry, Vol. 68, No. 1, January 1, 1996

and the obtained residue was purified by silica gel column
chromatography with hexane-ethyl acetate (9:1) as the eluent.
Further purification by HPLC using acetone as the eluent yielded
2,2,3,3,11,11,12,12-octamethyl-6-tetradecyl-1,4,7,10,13-pentaoxacy-
clohexadecane (C14-DTM16C5B; 180 mg, 18.3%) as a colorless
oil. Analytical data for C14-DTM16C5B are as follows: 1H-NMR
(270 MHz, CDCl3) δ 0.87 (t, 3H, -CH3), 1.14 and 1.18 (s, 24H, 8
-CH3), 1.20-1.56 (m, 26H, -CH2-), 1.69 (m, 2H, -CH2-), 3.30-
3.74 (m, 11H, -OCH2-). Anal. Calcd for C33H66O5 (542.89): C,
73.01; H, 12.25. Found: C, 72.98; H, 12.28.
evaporation of THF, the residue was extracted twice with
chloroform. The organic solvent was then evaporated, and the
obtained residue was purified by silica gel column chromatography
with hexane-ethyl acetate (9:1) as the eluent to yield 15-octadecyl-
1,4,7,10,13-pentaoxacyclohexadecane C18-16C5; 107.9 mg, 21.6%)
as a white crystal. Analytical data for C18-16C5 are as follows:
1H-NMR (270 MHz, CDCl3) and δ 0.87 (m, 3H, -CH3), 1.25 (s,
34H, 17 -CH2), 1.82 (b, 1H, -CH-), 3.44-3.72 (m, 20H, 10
-CH2-). Anal. Calcd for C29H58O5 (486.78): C, 71.56; H, 12.01.
Found: C, 71.58; H, 12.05.
(v) C1 4 -DD1 6 C5 (6 -Tetradecyl-2 ,6 ,1 3 ,1 6 ,1 9 -pentaoxa-
pentacyclo[18 .4 .4 .4 7,12.0 1.20.0 7,12]dotriacontane). NaH (220
mg, 5.40 mmol) was added to a solution of 1 1 (513.9 mg, 1.35
mmol) in THF (10 mL) and stirred at 40 °C for 1 h. A solution of
1 7 (619.4 mg, 1.35 mmol) in 12 mL of THF was then added to
this mixture. The mixture was then stirred at 70 °C for 3 days. A
small amount of methanol (12 mL) was added to quench the
excess NaH. After evaporation of THF, the residue was extracted
three times with ethyl acetate. The solvent was then evaporated,
and the obtained residue was purified by silica gel column
chromatography with hexane-ethyl acetate (9:1) as the eluent.
Further purification by HPLC using acetone as the eluent yielded
6-tetradecyl-2,6,13,16,19-pentaoxapentacyclo[18.4.4.47,12.01,20.07,12]-
dotriacontane (C14-DD16C5; 140.1 mg, 16.0%) as a colorless oil.
Analytical data for C14-DD16C5 are as follows: 1H-NMR (270
MHz, CDCl3) δ 0.87 (t, 3H, -CH3), 1.18-2.40 (m, 60H, -CH2-),
3.10-3.92 (m, 11H, -OCH2-). Anal. Calcd for C41H74O5
(647.04): C, 76.11; H, 11.53. Found: C, 76.51; H, 11.56.
(vi) Nor1 6 C5 (8 ,1 1 ,1 4 ,1 7 ,2 0 -P entaoxaspiro[5 .1 5 ]-1 ,4 -
methano-2-heneicosene). NaH (310 mg, 7.68 mmol) was added
to a solution of 2,3-bis(hydroxymethyl)-5-norbornene (493.6 mg,
3.2 mmol) in THF (10 mL) and stirred for 1 h at room temperature.
A solution of tetraethylene glycol ditosylate (1.609 g, 3.2 mmol)
in 10 mL of THF was then added to this mixture. The mixture
was then stirred at 70 °C for 20 h. A small amount of methanol
was added to quench the excess NaH. After evaporation of THF,
the residue was extracted twice with ethyl acetate. The solvent
was then evaporated, and the obtained residue was purified by
silica gel column chromatography with hexane-ethyl acetate (1:
2) as the eluent. Further purification by HPLC using methanol
as the eluent yielded 8,11,14,17,20-pentaoxaspiro[5.15]-1,4-methano-
2-heneicosene (Nor16C5; 253.8 mg, 25.38%) as a colorless oil.
Analytical data for Nor16C5 are as follows: 1H-NMR (270 MHz,
CDCl3) δ 0.70-0.80 (m, 1H, -CH-), 1.32-1.58 (m, 3H, -CH-,
-CH2-), 2.68 and 2.79 (br, 2H, -CH2-), 3.12-3.88 (m, 20H,
-OCH2-), 6.00-6.16 (m, 2H). Anal. Calcd for C17H28O5
(312.41): C, 65.36; H, 9.03. Found: C, 65.38; H, 9.07.
(vii) C1 8 -1 6 C5 (1 5 -Octadecyl-1 ,4 ,7 ,1 0 ,1 3 -pentaoxacy-
clohexadecane). Malonic acid diethyl ester (1.60 g, 9.98 mmol)
was added to the suspension of NaH (0.390 g, 9.9 mmol) in 20
mL of ethanol. A solution of 1-bromooctadecane (3.24, 9.7 mmol)
in 30 mL of ethanol was then added, and the mixture was refluxed
at 80 °C for 14 h. After evaporation of ethanol, the residue was
extracted three times with chloroform. The organic solvent was
evaporated, and the obtained residue was purified by silica gel
column chromatography (hexane-ethyl acetate 9:1) to yield
diethyl 2-octadecylmalonate (1 8 ; 1.91 g, 47.8%). Product 1 8
(420.6 mg, 1.02 mmol) was added to a suspension of LiAlH4 (58.0
mg, 1.53 mmol) in 5 mL of THF in an ice bath and stirred for 3
h. A small amount of water (1 mL) was then added to this mixture
to quench the reaction. After evaporation of THF, the residue
was extracted twice with chloroform to yield 2-octadecyl-1,3-
butanediol (1 9 ; 220 mg, 65.7%) as a white crystal. NaH (98.6 mg,
2.47 mmol) was added to a solution of 1 9 (336.47 mg, 1.03 mmol)
and stirred at room temperature for 1 h. A solution of tetraeth-
ylene glycol ditosylate (389.78 mg, 68.7 mmol) was then added,
and the mixture was refluxed at 80 °C for 14 h. A small amount
of methanol (10 mL) was added to quench the excess NaH. After
(viii) MD-1 6 C5 (2 , 5 , 8 , 1 1 , 1 5 -P entaoxatricyclo [1 4 .4 .
4 .0 ] tetracosane). To the DMF solution of triethylene glycol
(3.13 g, 20.8 mmol) in an ice bath was added NaH (1.25 g, 31.2
mmol), and the mixture was stirred for 30 min. Benzyl bromide
(3.56 g, 20.8 mmol) was then added to the reaction mixture. The
reaction mixture was then stirred at 80 °C for 2 h. A small amount
of methanol was added to quench the excess NaH. After
evaporation of DMF, the residue was extracted twice with ethyl
acetate. The organic solvent was then evaporated, and the
obtained residue was purified by silica gel column chromatography
with hexane-ethyl acetate (9:1) as the eluent to yield 8-(benzyl-
oxy)-3,6-dioxaoctanol (2 0 ; 2.83 g, 28.3%) as a colorless oil.
NaH (0.71 g, 17.7 mmol) was added to the THF solution of
2 0 (2.83 g, 11.8 mmol) in an ice bath and stirred for 30 min. Allyl
bromide (1.71 g, 1.2 mmol) was then added slowly to this mixture.
The reaction mixture was then refluxed for 2 h, and a small
amount of methanol was added to quench the excess NaH. After
evaporation of THF, the residue was extracted twice with ethyl
acetate. The organic solvent was then evaporated, and the
obtained residue was purified by silica gel column chromatography
with hexane-ethyl acetate (1:1) as the eluent to yield 12-
(benzyloxy)-4,7,10-trioxa-1-dodecene (2 1 ; 2.52 g, 76.1%) as a
colorless oil.
To the THF suspension of NaBH4 (0.139 g, 4 mmol) and BF3
ethereal complex (0.757 g, 5.33 mmol) was added a THF solution
of 2 1 (2.52 g, 9.0 mmol), and the mixture was stirred for 2 h. A
small amount of water was then added to this mixture, followed
by of 2.1 mL of NaOH (3 M) solution and 1.51 mL of 30% H2O2
solution, and this mixture was stirred for 2 h. The reaction
mixture was then extracted with ethyl acetate and the organic
solvent evaporated. The residue was purified by silica gel column
chromatography (hexane-ethyl acetate 9:1) to yield 12-(benzy-
loxy)-4,7,10-trioxadodecanol (2 2 ; 0.86 g, 32.5%).
To the methanol solution of 2 2 (583 mg, 1.95 mmol) was
added 10% Pd-C (291 mg, 50 wt %), and the reaction mixture
was stirred at room temperature under 1 atm H2 for 3 h. After
the solid was filtered off, the mixture was evaporated to yield 3,6,9-
trioxa-1,12-dodecanediol (2 3 ; 383 mg, 94.3%) as a colorless oil.
Tosyl chloride (1.052 g, 5.52 mmol) was added to a solution of
2 3 (383 mg, 1.84 mmol) in 10 mL of pyridine and stirred for 1 h
in an ice bath. The reaction mixture was then evaporated, and
the residue 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 (1:2) as the eluent to yield 3,6,9-trioxa-1,12-dodecanol
ditosylate (2 4 ; 612 mg, 64.4%) as a colorless oil. NaH (188.8 mg,
4.72 mmol) was added to a solution of cis-decalindiol (201 mg,
1.18 mmol) in THF (20 mL) and stirred for 1 h. A solution of 2 4
(612 mg, 1.18 mmol) in 7 mL of THF was then added to this
mixture and stirred at 70 °C for 24 h. A small amount of methanol
was added to quench the excess NaH. After evaporation of THF,
the residue was extracted twice with ethyl acetate. The organic
solvent was then evaporated, and the obtained residue was purified
by silica gel column chromatography (hexane-ethyl acetate 1:9)
to yield 2,5,8,11,15-pentaoxatricyclo[14.4.4.0] tetracosane (MD-
16C5; 40 mg, 10.0%) as a colorless oil. Analytical data for MD-
16C5 are as follows: 1H-NMR (270 MHz, CDCl3) δ 1.22-2.18 (m,
18H, dec-H and -CH2-), 3.30-3.88 (m, 16H, 8 -OCH2). Anal.
Analytical Chemistry, Vol. 68, No. 1, January 1, 1996 211

pot
Figure 2. Ion selectivity factors (log k , j is the interfering ion) of the electrodes based on 16-crown-5 derivatives as novel Na+-selective
Na,j
ionophores.
Calcd for C19H34O5 (342.48): C, 66.64; H, 10.01. Found: C, 66.67;
H, 10.04.
distribution coefficient between organic liquid and water), were
determined with Rf values of reversed-phase thin-layer chroma-
tography (RP-TLC) according to the method reported.2 The RP-
TLC used octadecylsilane-modified silica plates (KC18F, What-
man) that were cut to a length of 20 cm and developed
chromatographically with ethanol-water (9:1) as the mobile
phase.
Electrode P reparation and emf Measurements. Ion-
sensitive membranes of the PVC matrix type were prepared
according to the previously described procedures.6 The polymeric
membrane composition was normally 3 wt % ionophore, 67.9 wt
% membrane solvent BBPA, 29.1 wt % PVC, and 10 mol % (relative
to the ionophore) potassium tetrakis(p-chlorophenyl)borate (KT-
pClPB, Dojindo Laboratories, Kumamoto, Japan) unless otherwise
stated. The membrane thickness was ∼100 µm. A 6 mm
diameter circle was cut from a prepared membrane and placed
on the tip of the PVC ion-selective electrode body assembly
(Liquid Electrode Membrane Kit, DKK Co., Ltd., Tokyo, Japan).
The prepared electrodes were immersed in 0.1 M NaCl solution
for over 24 h for preconditioning before use. The external
reference electrode was a double-junction type Ag/ AgCl electrode
(HS-305DS, Toa Electronics, Ltd., Tokyo, Japan). The electrode
response potential (emf) measurements were performed according
to the reported procedure at 25 ( 0.5 °C using the electrochemical
cell system,6
RESULTS AND DISCUSSION
Structural Ion Selectivity Features of 1 6 -Crown-5 Deriva-
tives. Based on the molecular model shown in Figure 1, we have
designed and synthesized eight kinds of 16-crown-5 compounds,
and their ion selectivity features were examined with an ion-
selective electrode method using these ionophores. Figure 2
shows the ion selectivity coefficients of the electrode based on
these synthesized ionophores, and their chemical structures are
also indicated in Figure 2.
One of the synthesized ionophores, C18-16C5, having a normal
alkyl group as a lipophilic side chain in the normal 16-crown-5, is
not a good fit for this model. In fact, the electrode based on C18-
16C5 was more selective for Rb+ than for Na+. The ionic diameter
of Rb+ is ∼2.9 Å, and therefore it does not fit in the cavity of
16-crown-5 (1.8-2.4 Å). Because the octadecyl group (normal
alkyl group) in the C18-16C5 cannot function as the block subunit,
this ionophore preferably forms a 1:2 Rb+-ionophore sandwich
complex.
Comparing the ion selectivity of the electrode based on
Nor16C5 and MD16C5, which has one bulky subunit, it is clear
that a greater block effect can be found by introducing the bulky
group into the ethylene part rather than in the pivotal position of
the propylene part of the crown ether ring. It is true that the
norbornene group is sterically very bulky, but the electrode based
on Nor16C5 did exhibit selectivity for alkali metal ions with larger
ionic diameter than that of Na+. We have fully discussed this
structural feature in our previous report on highly selective
ionophores for Li+,5 i.e., that introducing a bulky block subunit
close to the binding site oxygen atom in the crown ether
compound gave a better block effect. On the other hand, a
Ag|AgCl|3 M KCl||0.3 M NH4NO3||test solution|
membrane|0.1 M NaCl|AgCl|Ag
All test solutions were made from chloride salts without any pH-
pot
adjusting buffer reagent. The selectivity coefficients
k , where
ij
i is the primary ion (Na+) and j is the interfering ion, were
calculated from the response potentials in an alkali metal or
alkaline earth metal chloride solution using the fixed interference
method (FIM; j ) 0.1 M) according to the recommendations of
IUPAC and JIS.7,8
Determination of Lipophilicities of Ionophores. The lipo-
philicities of several synthesized ionophores, log Po/ w (Po/ w is the
(6) Suzuki, K.; Tohda, K.; Aruga, H.; Matsuzoe, M.; Inoue, H.; Shirai, T. Anal.
Chem. 1 9 8 8 , 60, 1714.
(7) IUPAC Recomendation for Nomenclature of Ion-Selective Electrodes. Pure
Appl. Chem. 1 9 7 6 , 48, 29.
(8) JIS K-0122, Japanese Standards Association, Tokyo, 1981.
212 Analytical Chemistry, Vol. 68, No. 1, January 1, 1996

group and a decalino group are understandable when one
compares the heights of their bulky blocking walls in the crown
ring plane and their rigid structures. The lipophilicity of DD16C5
was log Po/ w) 11.8, and this value fulfills the requirement for
application in the analysis of human serum (log Po/ w ) 11.3),2
while the log Po/ w value for DTM16C5B is 6.3-6.4, not sufficiently
lipophilic for the analysis. Thus, C14-DTM16C5, which has a long
alkyl group (tetradecyl group) introduced into the DTM16C5, was
synthesized. This compound exhibited a log Po/ w value of 12.4.
Comparing the ion selectivities of DTM16C5B and C14-DTM16C5,
it was observed that the latter ionophore exhibited slightly better
Na+ selectivity relative to all other tested cations, as shown in
Figure 2. This result indicates that the tetradecyl group showed
the block effect to some extent.
Similarly, C14-DD16C5, a DD16C5 derivative having a tetrade-
cyl group as the lipophilic side chain was also synthesized. The
log Po/ w value of C14-DD16C5 was very high (20.4), but its Na+/
K+ selectivity was slightly lower compared to that of DD16C5.
This fact indicates that introduction of additional numbers of block
subunits into DD16C5 resulted in a negative effect on the Na+/
K+ selectivity, which interfered with the cavity space fit of Na+. A
similar result was observed in the investigation of the lithium
ionophore design based on 14-crown-4.5 Thus, it is understandable
that for a sodium ionophore design based on 16-crown-5, there is
also a suitable position and an optimum number of block subunits
in the crown ring.
Optim ization of the Electrode Mem brane Based on
DD1 6 C5 and Its Response Characteristics. Among eight
kinds of newly synthesized ionophores, DD16C5 exhibited the
best Na+ selectivity relative to other tested cations. Thus, in order
to find the best response membrane composition, we conducted
an optimization study using DD16C5 as an ion-sensing component
for the electrode membrane. In the case of the electrode
membrane employing BBPA as a low polarity membrane solvent
(ꢀ ) 4; ꢀ is the dielectric constant), when the quantity of the
ionophore DD16C5 was varied to 1, 3, 5, 10, and 20 wt %, the
resulting ion selectivity features were not varied significantly in
these electrodes (in the case where the DD16C5 content in the
membrane was >20 wt %, the membrane plasticity was decreased
and the strength of the membrane was reduced). The lipophilic
anionic additive, KTCPB, was added to the electrode membrane
to prevent anionic interference from the test solution; however, if
the addition is too much, it will decrease the selectivity for the
primary ion, because KTCPB acts as a cation exchanger in its
anion form (TCPB-). When the quantity of KTCPB was varied
to 5, 10, 20, 30, 50, and 100 mol % relative to the molar quantity
of the ionophore, it was observed that 5-10 mol % is the optimum
quantity of KTCPB to be added to the electrode membrane based
on DD16C5. When the quantity of KTCPB was 20 mol % and
30-50 mol %, ∼8% and 10-20% decreases were observed in the
Na+/ K+ selectivity, respectively. For the membrane with 100
mol% KTCPB, the electrode membrane selectivity was close to
the selectivity of the TCPB anion itself, for which the Na+/ K+
selectivity was only approximately 2.
As for the plasticizer for the PVC matrix membrane, besides
BBPA which has been discussed up to this point, we have also
examined three other types of membrane solvents (plasticizers):
DBE, NPOE, and TEHP. BBPA, which is often used in practical
applications, is a highly lipophilic ester-type plasticizer with low
polarity (ꢀ ) 4); DBE is an ether-type plasticizer with low polarity
(ꢀ ) 4); and NPOE is a relatively high polarity ether-type
plasticizer (ꢀ ) 24). TEHP is a phosphate-type ester, and it is
known that the PdO group in the phosphate has a relatively
strong ability to bind alkali metal ions such as Li+.10 Among these
three membrane solvents (BBPA, DBE, and NPOE), the electrode
using BBPA as the membrane solvent exhibited a slightly better
Na+ selectivity, but the electrode using TEHP as a membrane
Figure 3. Space-filling (CPK) model views of DTM16C5B (a) and
DD16C5 (b).
decalino group in the ethylene part in the crown ether is a very
effective block subunit. The electrode based on MD16C5 showed
Na+/ K+ and Na+/ Rb+ selectivities of 40 and 160, respectively, and
it is obvious that introduction of a decalino group has lowered
the stability of the sandwich complex.
We have reported another highly effective block subunit: a
2,2,3,3-tetramethyl group (abbreviated as “tetramethyl group”)
similar to that of the decalino group. We designed two derivatives
of 16-crown-5 having two tetramethyl groups and synthesized
DTM16C5A and DTM16C5B. Considering of the preparation
procedures, facilitated by a procedure developed recently by
Sachleben et al.,9 the total synthetic yield of DTM16C5B obtained
was much higher than that of DTM16C5A. The electrodes based
on these two derivatives did not show considerable differences
in their ion selectivity features, as shown in Figure 2. The Na+/
K+ selectivity of these electrodes is 100-130; that is, 2-3 times
more Na+-selective compared to the electrode based on 16-crown-5
having one decaline group, MD16C5. With the introduction of
two block subunits into the 14-crown-4 as a Li+ ionophore, a
positive block effect is not observed in the Li+/ Na+ selectivity.5
On the contrary, it is obviously effective to introduce two block
subunits into the Na+ ionophore based on 16-crown-5.
The 16-crown-5 derivative with two decalino groups, DD16C5,
showed a Na+/ K+ selectivity of over 300. This selectivity is about
3 times that of MD16C5, which has one decalino group. As shown
in Figure 3 for the CPK models of DTM16C5B and DD16C5, the
differences in effectiveness of the block effect with a tetramethyl
(9) Sachleben, R. A.; Davis, M. C.; Bruce, J. J.; Ripplr, E. S.; Driver, J. L.; Moyer,
B. A. Tetrahedron Lett. 1 9 9 3 , 34, 5373-5376.
(10) Kimura, K.; Oishi, O.; Murata, T.; Shono, T. Anal. Chem. 1 9 8 7 , 59 , 2331.
Analytical Chemistry, Vol. 68, No. 1, January 1, 1996 213

pot
Na,j
Figure 4. Ion selectivity factors (log k , j ) interfering ion) of the electrodes based DD16C5 with different membrane solvents (DBE,
dibenzyl ether; NPOE, 2-nitrophenyl octyl ether; TEHP, tris(ethylhexyl) phosphate).
solvent showed better Na+ selectivity, even compared to that based
on BBPA, as shown in Figure 4. The Na+/ K+ selectivity of the
electrode based on DD16C5 and TEHP was 1000; therefore, it is
one of the best Na+ electrodes reported to date. This membrane
solvent, TEHP, was also tested for the Li+ electrode based on a
highly Li+-selective ionophore, monodecalino-14-crown-4. How-
ever, a positive result was not observed in its ion selectivity
features, including Li+/ Na+ selectivity.5 In the case of 14-crown-4
as a Li+ ionophore, the coordination number of 4 is the best fit
for a small ion (Li+), so the other binding site offered by the
solvent molecule (TEHP) was not needed. On the contrary, in
the case of the Na+ ionophore based on 16-crown-5, even in the
case of DD16C5, the TEHP molecule effectively coordinates with
Na+, together with the ionophore which has five oxygens. As
shown in Figure 4, when 2 wt % TEHP was used with BBPA, DBE,
or NPOE as the membrane solvent, an increase in Na+/ K+
selectivity was also observed. In relation to this fact, the following
two subjects are considered to affect Na+ coordination: (1) The
coordination number 5 offered by the 16-crown-5, which is the
lowest suitable number for Na+. In fact, some bis(benzo-12-crown-
4) compounds have a coordination number of 8.11 (2) The larger
Figure 5. Typical response curves for Na+ obtained with the
the ring size in the crown compound, the larger will be the open
space in the upper and lower sides of the crown ether plane. The
16-membered crown does not have a large ring size, but the space
fit for the PdO in the TEHP molecule to coordinate with the
DD16C5-Na+ complex is sterically possible.
electrode based on DD16C5. Curves a and b indicate the response
curves for Na+ with and without interfering ions, respectively, similar
to the normal ion concentration levels of human intracellular fluid (120
mM K+, 2 mM Li+, 3 mM Mg2+, and 1 mM Ca2+).
The response of the electrode based on DD16C5 and TEHP
to a human blood fluid level Na+ concentration was examined.
The response curve of the electrode in test solutions containing
120 mM K+, 2 mM Li+, 3 mM Mg2+, and 1 mM Ca2+, a
composition similar to that of a typical normal human intracellular
fluid,1 showed an almost Nernstian response down to a Na+
Until recently, in relation to the development of a Na+-selective
electrode, many ionophores for Na+, including diamide,12,13 hem-
ispherand,14 biscrown,10,11 monensin derivative,15,16 calixarene,17-20
and 16-crown-5 derivatives,3,21,22 were synthesized and utilized as
concentration of 10-4 M, as shown in Figure 5. The mathemati-
pot
Na,K
(12) Anker, P.; Jenny, H. B.; Wuthier, U.; Asper, R.; Ammann, D.; Simon, W.
Clin. Chem. 1 9 8 3 , 29, 1508.
(13) Gehrig, P.; Rusterholz, B.; Simon, W. Anal. Chim. Acta 1 9 9 0 , 233, 295.
(14) Toner, J. L.; Daniel, D. S.; Geer, S. M. U.S. Patent 4,476,007, Oct 9, 1984.
(15) Tohda, K.; Suzuki, K.; Kosuge, N.; Nagashima, H.; Watanabe, K.; Inoue,
H.; Shirai, T. Anal. Sci. 1 9 9 0 , 6, 227.
(16) Suzuki, K.; Tohda, K. Trends Anal. Chem. 1 9 9 3 , 12, 287.
(17) Diamond, D.; Svehla, G.; Seward, E. M.; McKervey, M. A. Anal. Chim. Acta
1 9 8 8 , 204, 223.
cally calculated required selectivity coefficient of log
k
for the
determination of Na+ in a human intracellular fluid is -3.5, with
1% error in the worst case.1 The electrode based on DD16C5 and
TEHP could determine the Na+ in a human intracellular fluid. In
addition, with this response curve in Figure 5, a Na+/ K+ selectivity
of over 1000 was also determined.
(11) Shono, T.; Okahara, M.; Ikeda, I.; Kimura, K.; Tamura, H. J. Electroanal.
Chem. 1 9 8 2 , 132, 99.
(18) Kimura, K.; Matsuo, M.; Shono, T. Chem. Lett. 1 9 8 8 , 615.
214 Analytical Chemistry, Vol. 68, No. 1, January 1, 1996

the Na+ sensing component for the electrode. In these reported
a very important role in providing a large positive effect on the
ion-selective characteristic of the ionophore molecule, is unfor-
tunately not yet a common useful factor in the host molecule
design. However, in the near future, most of the reseachers
involved in host-guest chemistry will recognize the importance
of this subject. Using a methodological approach similar to that
discussed in the present research, we have also successfully
data, only the calixarene-type ionophore had a Na+/ K+ selectivity
pot
Na,K
of more than 1000 (log
k
< -3.0).20 But, unfortunately, our
examination of the electrode obtained from the developer showed
a different selectivity value (log kpot Na,K ) -2.6 to 2.8) compared
pot
to the reported value (log
k
< -4.0). In our opinion, they
Na,K
omitted the preconditioning step using an electrolyte containing
Na+, so they actually measured the non-steady-state potential
response values.
developed highly selective ionophores for Li+, Ca2+, and Mg2+
.
The appropriate ionophore design and synthesis could be realized
to offer many useful chemical ion sensors having high selectivity
for analytes, such as selectivities of over 1000 relative to other
interferents.5,23
CONCLUSIONS
In this report, we propose a simple Na+ ionophore molecular
model and successfully develop a highly selective ionophore for
Na+ based on this model. The examination of the ionophore
chemical structures and their ion selectivity features contributes
to host-guest chemistry, especially for alkali metal cation ligand
or complex design. In this case, the block subunit, which plays
ACKNOWLEDGMENT
Partial support of this investigation by The Salt Science
Research Foundation, The General Sekiyu Research & Develop-
ment Encouragement & Assistance Foundation, The Izumi Sci-
ence and Technology Foundation, and the Ministry of Education
is acknowledged.
(19) Kimura, K.; Matsuba, T.; Tsujimura, Y.; Yokoyama, M. Anal. Chem. 1 9 9 2 ,
64, 2508.
Received for review August 2, 1995. Accepted October
18, 1995.X
(20) Yamamoto, H.; Shinkai, S. Chem. Lett. 1 9 9 4 , 1115.
(21) Ohki, A.; Lu, J. P.; Bartsch, R. A. Anal. Chem. 1 9 9 4 , 66, 651.
(22) Ohki, A.; Lu, J. P.; Huang, X.; Bartsch, R. A. Anal. Chem. 1 9 9 4 , 66, 4332.
(23) Suzuki, K.; Watanabe, K.; Matsumoto, Y.; Kobayashi, M.; Sato, S.; Siswanta,
D.; Hisamoto, H. Anal. Chem. 1 9 9 5 , 67, 324.
AC950773J
X Abstract published in Advance ACS Abstracts, December 1, 1995.
Analytical Chemistry, Vol. 68, No. 1, January 1, 1996 215