Anal. Chem. 1988, 58,2285-2289
10 rnV
4
S STIRRING
0
5
10
15
20
[s]TIME
Flgure 8. Emf response of a cell assembly based on ETH 129 to a
change in concentration from 3 X lo3 M to io-' M CaCI,.
for a high selectivity. Using the nonmacrocyclic neutral carrier
E T H 129 and current membrane technology, solvent polymeric membranes exhibiting the highest so far reported
membrane selectivities for metal cations have been realized.
The extreme ion selectivity (108) and low detection limit (100
pM Ca2+)open several new aspects in Ca2+analysis. If these
properties can be taken advantage of in microelectrodes, intracellular studies of sub-micromolar Ca2+activities will become more reliable and versatile. Furthermore, the sensor
is especially suited for other low-level Ca2+measurements, e.g.,
the detection of <lo4 M Ca2+concentrations a t pH 5 4 in soil
chemistry.
Registry No. ETH 129, 74267-27-9; Ca, 7440-70-2.
LITERATURE CITED
(1) Thomas, J. D.R. Anal. Proc. (London) 1985, 2 2 , 356.
(2) Simon, W.; Ammann, D.; Oehme, M.; Morf, W. E. Ann. N . Y . Acad.
Sei. 1978, 307, 52.
2285
(3) Moody, 0. J.; Thomas, J. D. R. Ion-Sel. Ekctrode Rev. 1079, 1 , 3.
(4) Petranek, J.; Ryba, 0. Anal. Chlm. Acta 1881, 128, 129.
(5) Kimura, K.; Kumami, K.; Kbzawa, S.; Shono, T. J . Chem. Soc.,
Chem. Commun. 1984, 442.
(6) Ammann, D.; GUggi, M.; Pretsch, E.; Simon, W. Anal. Lett. 1875, 8 ,
709.
(7) Ammann, D.; Morf, W. E.; Anger, P.; Meier, P. C.; Pretsch, E.; Simon,
W. Ion-Sel. Electrode Rev. 1983, 5 , 3.
(6) Meier, P. C.; Lanter, F.; Ammann, D.; Steiner, R. A.; Simon, W.
Pfliigefs Arch. 1982, 393, 23.
(9) Yu, T. R.. private communication.
(10) Yu, T. R. Ion-Sel. ElecfrodeRev. 1985, 7 , 165.
(11) Pretsch, E.; Ammann, D.; Osswald, H. F.; GOggi, M.; Simon, W. Helv.
Chim. Acta 1080, 63. 191.
(12) Neupert-Laves, K.; Dobier, M. J . Cfystallcgr. Spectrosc. Res. 1982,
12, 287.
(13) Meier, P. C.; Morf, W. E.; Uubli, M.; Simon, W. Anal. Chlm. Acta
1984, 156, 1.
(14) Anker, P.; Wieland, E.; Ammann. D.; Dohner, R. E.; Asper, R.; Simon,
W. Anal. Chem. 1881, 53, 1970.
(15) Ammann, D.; Bissig, R.; Giiggi, M.; Pretsch. E.; Simon, W.; Borowttz, I .
J.; Weiss, L. Helv. Chlm. Acta 1975, 5 8 , 1535.
(16) Dohner, R. E.; Wegmann, D.; Morf, W. E.; Simon, W. Anal. Chem., in
press.
(17) Henderson, P. 2.Phys. Chem. 1907, 5 9 , 118.
(18) Henderson, P. 2.Phys. Chem. 1008, 63, 325.
(19) Meler, P.C. Anal. Chlm. Acta 1982, 136, 363.
(20) RdZiEka, J.; Hansen, E. H.; Tjell, J. C. Anal. Chlm. Acta 1973, 67.
155.
(21) Tsien, R. Y.; Rink, T. J. J . Neurosci. Methods 1981, 4 , 73.
(22)
. . Gddschmidt. V. M. Skr. Nor. VMensk.-Akad., IKI.1
- - 1 : Mat.-Nefurvidsnsk. Kl. 1928.
(23) Mod. W. E.; Slmon, W. Helv. Chlm. Acta 1971, 5 4 , 2683.
(24) Simon, W.; Ammann, D.; Pretsch, E.; Morf, W. E.; Oesch, U.; Huser,
M.; Schulthess, P. Proceedings of the International Symposium on Ion
Transport Through Membranes, Nagoya, Japan, 1986, in press.
(25) Simon, W.; Morf. W. E.; Meier, P. C. Struct. Bonding (8erlh) 1973,
16, 113.
(26) Dietrich, B.; Lehn, J.-M.; Sauvage, J. P. Tetrahedron Lett. 1969, 3 4 ,
2885.
(27) Lehn, J.-M. Pure Appl. Chem. 1080, 52, 2441.
(28) Pedersen, C. J. J . Am. Chem. SOC. 1867, 89, 2495.
(29) VGgtle, F.; Weber, E.; Eiben. U. Konfakfe (Darmsfadt) 1980, 2 , 36.
RECEIVED
for review February 18,1986. Accepted April 28,
1986. This work was partly supported by the Swiss National
Science Foundation, by Nova Biomedical Corp., and by Orion
Research, Inc.
Design of Neutral Hydrogen Ion Carriers for Solvent Polymeric
Membrane Electrodes of Selected pH Range
Urs Oesch, Zbigniew Brzbzka,' Aiping Xu: Bruno Rusterholz, Gabriela Suter, Hhng Viet Pham,
Dieter H. Welti, Daniel Ammann, Em6 Pretsch, and Wilhelm Simon*
Department of Organic Chemistry, Swiss Federal Institute of Technology (ETH), Universitatstrasse 16,
CH-8092 Zurich, Switzerland
A series of new neutral canlers for hydrogen ions are used
in solvent polymeric membrane (SPM) pH electrodes. Their
dynamlc pH range is directly related to the acidity constant
of the active site of the ionophore. Further features for designing a SPM based pH electrode of broad and selected
dynamk range are diwmsed. On this basis a neutral carrier
based membrane electrode for hydrogen bns with a dynamic
pH range from 8 to 0 is introduced.
O n leave from the Department o f Chemistry, Technical Universit of Warsaw, U1.Noakowskie o 3, PL-00-664Warsaw, Poland.
2&
leave from the Hygiene j e p a r t m e n t of Nanjing Medical
College, Nanjing, People's Republic o f China.
0003-2700/86/0358-2285$01.50/0
In view of ease of preparation, low electrical resistance, and
handling safety, there is a considerable interest in nonglass
systems for clinical pH measurements for intravascular and
intraluminal applications. For this purpose, classical electrically charged ion carriers have been introduced for use in
solvent polymeric membranes (1-4). Neutral carriers such
as tri-n-dodecylamine induce much higher selectivities (5) and
have therefore found wide application in microelectrodes for
intracellular studies (6, 7), in solvent polymeric membranes
for blood pH measurement (81,and in sensors for a variety
of other assays (+13). Although the obtained sensor selectivities are very impressive (log KP&, = -10.4, log KPi = -9.8,
KZa < -11.1 (5)),they are still inferior as compared to glass
0 1986 American Chemical Society
2286
ANALYTICAL CHEMISTRY, VOL. 58, NO. 11, SEPTEMBER 1986
electrodes. The cation interference imposes limitations in their
use at high pH values and the anion interference sets a limit
at the lower end of the p H scale. Since the extent of loading
of a neutral carrier with the transported ion is relevant for
its behavior in ion-selective electrodes (141, it can be assumed
that the pH range for the application of a hydrogen ion selective sensor will depend on the acidity constant (pK) of the
incorporated ionophore (5).
Here we report on the design of neutral hydrogen ionophores for ion-selective electrodes applicable in a distinct p H
range. The constitutions of the new ionophores have been
selected to cover a wide pK range as well as to exhibit high
lipophilicities in view of a high sensor lifetime (15). We report
further about the design features of such solvent polymeric
membrane pH electrodes for an improvement, Le.. an extension, of the applicable pH range.
EXPERIMENTAL SECTION
Membrane Materials. High molecular weight poly(viny1
chloride) (PVC), potassium tetrakis(p-chloropheny1)borate
(KTpClPB), tridodecylamine (TDDA, ionophore 1 (Figure I)),
o-nitrophenyl octyl ether (0-NPOE), dibutyl phthalate (DBP),
bis(2-ethylhexyl) sebacate (DEHS), decane-1,lO-diyl bis(1-butylpenty1)glutarate (ETH 469 (16)) and tris(2-ethylhexyl) phosphate (TEHP) have been obtained from Fluka, Buchs, Switzerland. Tritetradecylamine (TTDA, ionophore 2) and trihexadecylamine (THDA, ionophore 3) were purchased from ICN
Pharmaceuticals Inc., Plainview, NY. 2-Octadecyloxyaniline
(ODA) originates from Alfred Bader Library of Rare Chemicals,
Aldrich Co., Inc., Milwaukee, WI. The synthesis of the plasticizer
3,3',4,4'-benzophenonetetracarboxylic acid tetra-n-undecyl ester
(BTCU) will be reported elsewhere (17). The syntheses of ionophores 4-6 are described in ref 13.
Syntheses of Ionophores 7-9 and 11. Ionophore 8 (l-octadecanoyl-4-methylpipermine)was obtained by the reaction (1 h,
0 OC) of equimolar amounts of 1-methylpiperazine (Fluka) with
freshly distilled stearoyl chloride (Fluka) in dry tetrahydrofuran
(THF) in the presence of an equimolar amount of triethylamine.
The solution was filtered and evaporated. The residual crude
product was redissolved in chloroform. This solution was first
washed with 0.1 N aqueous sodium hydroxide and then dried with
solid anhydrous magnesium sulfate. Purification by flash chromatography (silica gel, acetone) gave pure ionophore 8 (mp 52
"C; 25% yield). Anal. Calcd for 8: C, 75.35; H, 12.65; N, 7.64.
Found C, 75.21; H, 12.54; N, 7.51.
The synthesis of ionophore 9 (l-octadecanoyl-4-(2-pyridyl)piperazine) was done as for ionophore 8 using 1-(2-pyridy1)piperazine (EGA Chemie, Steinheim, GFR) as starting material.
Purification was performed by recrystallization from ethyl acetate
(mp 77 "C; 64% yield). Anal. Calcd for 9: C, 75.47; H, 11.03;
N, 9.78. Found: C, 75.68; H, 11.37; N, 9.58.
Ionophore 7 (N-octadecylmorpholine) was prepared by a
two-step reaction over N-octadecanoylmorpholine, which was
prepared from morpholine (Fluka) according the description for
ionophore 8. N-Octadecanoylmorpholine was then reduced (30
min a t 0-5 "C and additional 2 h a t room temperature) with an
equimolar amount of LiAlH, in dry diethyl ether. After the
addition of water and 1 N aqueous sodium hydroxide the suspension was filtered and evaporated. The crude product was
purified by flash chromatography (silica gel, ethyl acetate) and
distillation (160-170 "C, 0.07 mmHg) to yield pure ionophore 7
(mp 39-40 "C;34% yield). Anal. Calcd for 7: C, 77.81; H, 13.36;
N, 4.12. Found: C, 77.60; H, 13.18; N, 4.08.
Ionophore 11 (octadecyl isonicotinate) was obtained by reaction
of equimolar amounts of isonicotinoyl chloride (crude product
from reaction of isonicotinic acid (Fluka) and freshly distilled
thionyl chloride in toluene (6 h, 120 O C reflux)) and 1-octadecanol
and triethylamine in toluene (16 h, room temperature). After
addition of diethyl ether the solution was filtered and evaporated.
The residue was redissolved in diethyl ether and three times
washed with water. Recrystallization from ethyl acetate/ hexane
(4:l) yielded pure ionophore 11 (mp 57.5 "C; 15% yield). Anal.
Calcd for 11: C, 76.75; H, 11.00; N, 8.73. Found: C, 76.70; H,
11.10; N, 3.71.
The constitutions of all synthesized ionophores have been
confirmed by 'H NMR (300 MHz, CDCl,), I3C NMR (25 MHz,
CDCl,), IR (CHClJ, and MS and the purities have been determined by HPLC (PL gel 100, THF, RI detection).
Lipophilicities. The lipophilicities P of the ionophores have
been determined by thin-layer chromatography (TLC) using
reverse phase silica plates (KC 18 F, Whatman, Clifton, NJ) and
ethanol/water (9010) as eluent. The retention/lipophilicity
correlation has been calibrated with a set of components of known
lipophilicities (18). Due to the extreme extrapolation on the basis
of the calibration components (0 < log P < 6), the uncertainties
values amount from f1.4 (ionophore
of the determined log PTLc
9,log PTLC
= 10.8) UP to *9 (THDA, log P T L c == 43).
Membrane Preparation. The membrane components (1wt
% ionophore, 30 wt % PVC, -70 mol % KTpClPB (with respect
to the ionophore), and -69 wt % plasticizer) totaling 200 mg were
dissolved in 2 mL of freshly distilled THF. This solution has been
cast into a 24 mm i.d. glass ring resting on a glass
~. plate. After
overnight solvent evaporation, the resulting membrane was peeled
off from the glass mold and disks of 7 mm diameter were cut out.
The membrane disks were mounted in electrode bodies (type IS
561, Philips, Eindhoven, The Netherlands) for emf measurements.
Emf Measurements. All measurements were carried out at
20 "C with cells of the type Hg, Hg2C12;KC1 (satd)l3 M KClIsamp1e)Jmembranel)internal
filling solution; AgC1, Ag. A citrate
buffer of pH 5.6 (1 M citric acid, 2.73 M NaOH, 0.01 M NaC1)
has been used as internal filling solution throughout. The potentials have been recorded by a custom made 16-channel electrode monitor (resolution -120 pV) equipped with one FET
operational amplifier AD 515 KH per channel (Analog Devices,
Norwood, MA; input impedance l O I 3 0/2 pF; input bias current
<150 fA; capacity neutralization). The data acquisition was
performed with an Intel Data System (Intel Corp., Santa Clara,
CA) in combination with a display terminal, ADDS Regent 20
(Applied Digital Data Systems, Inc., Hauppauge, NY), and a
Wenger Print Swiss Matrix Printer (Wenger Datentechnik, Basel,
Switzerland), and our own software. Off-line processing was
performed on a Hewlett-Packard HP-9830 calculator system.
The membrane electrode function as well as that of a pH glass
electrode (Philips GA 110, Eindhoven, The Netherlands) has been
determined by adding stepwise 4 N hydrochloric acid into the
sample buffer (see below). For the presentation of the electrode
response, the emf of the membrane electrode is plotted against
the pH of the buffer solution measured by the glass electrode.
The emf of the membrane electrode is not corrected for the
diffusion potential of the liquid junction of the reference electrode,
since the measured emf of the glass electrode is influenced in the
same manner, thus canceling out by a direct comparison. The
pH glass electrode has been calibrated with standard buffers of
pH 4.00 and 6.88 (19). The electrical membrane resistance was
determined by use of the method of potential attenuation by
known shunt (15).
Buffers. The buffer solutions for the determination of the
electrode functions have been (a) a citrate/borate buffer with a
cationic background of 60 mM Lit (60 mM LiOH, 6.6 mM citric
acid, and 11.4 mM boric acid), (b) a Tris buffer with 140 mM of
Na+ (10 mM NaOH, 130 mM NaC1, and 10 mM of tris(hydroxymethy1)aminomethane (Tris)), and (c) a Tris buffer with 200
mM K+ (190 mM KCl, 10 mM KOH, and 10 mM of Trisj.
pK Determinations. The pK of the short-chain homologues
of the ionophores (Figure 1) have been determined by aqueous
titration (Titroprocessor 636/Dosimat E 635, Metrohm, Herisau,
Switzerland) at constant ionic strength ( I = 0.1 M) (sample, 0.1
M NaCl and 0.01 M amine; titrant, 0.1 M HCl). The used short
chain homologues have been triethylamine (Fluka) for ionophores
1-3, 2-(dimethy1amino)ethanol(Fluka) for ionophore 4, ( - 1 4 methylephedrine (Fluka) for ionophore 5, N,N,N',N'-tetramethylethylenediamine (Fluka) for ionophore 6, N-ethylmorpholine (Fluka) for ionophore 7,o-phenetidine (Fluka) for
ionophore 10, methyl isonicotinate (Flukaj for ionophore 11,
1-acetyl-4-methylpiperazinefor ionophore 8, and 1-acetyl-4-(2pyridy1)piperazine for ionophore 9. The latter two homologues
have been synthesized analogously to the descriptions given above.
NMR Experiments. Four milliliters of CDCl, containing 2.5
wt '70 dissolved ionophore was shaken vigorously with 4 mL of
water containing a varying amount of HCl. After 4 h the pH of
ANALYTICAL CHEMISTRY, VOL. 58, NO. 11, SEPTEMBER 1986
2287
IONOPHORE -I_
0-NPOE
KTpClPB
PVC
B
1.20 M K*
DYNAMIC
RANGE
1.14 M Na'
a
4
-
&-
,I
1
14
5
-
1
12
1
1
10
1
1
8
1
1
6
1
1
4
1
l
2
1
p
Flgure 2. Emf response of a solvent polymeric membrane electrode
contalnlng Ionophore 7 to the pH of three buffers wlth different cation
r - - -
"I
'Y
1
backgrounds as indicated (see Experimental Section for detailed buffer
composltlons). The pH of the buffer is determined by a pH glass
electrode. The definition used here for the dynamic range of the
electrode is illustrated for the buffer with Na+ background (circles).
6
-
where hHB and tiB denote the chemical shifts of the protonated
ionophore and the unprotonated ionophore, respectively, and 6
denotes the chemical shift of a mixture of them.
&-I
@to
RESULTS AND DISCUSSION
A typical electrode response of a solvent polymeric mem8
-
9
-O
0
Y
Figure 1. Constitutions of the ionophores discussed.
the water phase was measured with a pH glass electrode. The
initial amount of HCl was selected to achieve equilibrium pH
values between 6 and 0. The CDC13phase was transferred into
a 10 mm 0.d. NMR tube for recording a *%NMR spectrum (50.32
MHz, Bruker WP 200 SY FT spectrometer, Fallanden, Switzerland).
The chemical shifts (6 [ppm] relative to MelSi as internal
standard) of the a-CH2 to N (ionophore l), of the P-CH, to N
(ionophore 5), of the a-CH2to 0 (ionophore 7), and of the 7-C
to N (ionophore ll),were measured as a function of the pH of
the water phase. The fraction a of the protonated ionophore in
CDC13 was then calculated by
a=-
6 - 6B
8HB
- 6B
brane based on a hydrogen ion ionophore to the pH of a
sample solution is given in Figure 2. Here we define the
dynamic range of the membrane electrode as the pH range
extending from the lower to the upper detection limit as it
is illustrated for the 0.14 M Na+/Tris buffer background in
Figure 2. The lower detection limit (at high pH) is given by
the cation interference and therefore varies depending on the
cation background used in the buffered samples. The upper
detection limit (at low pH) is controlled by anion interference
(4).
As expected, a more lipophilic cation M leads to a more
severe interference, which is equivalent to a larger potentiometric selectivity factor K?;. The selectivity factors log
KFAcan be calculated from the electrode functions as depicted
in Figure 2 (fixed interference method (20)). For the cell
assembly described therein log KE& amounts to -9.4, -10.5,
and <-11.2 for M = K+, Na+, and Li+, respectively.
Electrode functions as given in Figure 2 for ionophore 7 have
been determined for all the ionophores presented in Figure
1. The dynamic ranges of the corresponding membrane
electrodes in the three buffers used are displayed in Figure
3 in dependence of the pK of the employed ionophore (Table
I). Ionophores 2 and 3 show dynamic ranges only marginally
deviating from ionophore 1 as anticipated on the basis of their
constitutions. They are therefore not displayed.
The slopes of the linear part of the dynamic ranges have
been found to be in all cases between 56.6 mV and 58.7 mV.
The electrical resistance of all the electrodes used have been
measured to be the range of 30 kR to 1mR. The response time
(tea%) of the electrodes upon addition of hydrochloric acid
to the stirred and buffered sample has been typically a few
seconds in all cases. Due to the limited water solubility of
2288
ANALYTICAL CHEMISTRY, VOL. 58, NO. 11, SEPTEMBER 1986
FRACTION OF THE PROTONATED IONOPHORE IN COCI,
d (
1A
05-
00
31
12
4
8
10
4
6
2
I
0 PH
DYNAMIC RANGE
Flgure 3. Dynamic pH range of solvent polymeric membrane eiectrodes containing different hydrogen ion ionophores in three buffers
with different but constant cation background in relation to the p K of
the corresponding short-chain homologue of the ionophore. I n cases
where the last or first point of the experimental electrode function is
still or already, respectively, on its linear portion, the uncertainty of the
end of the dynamic range is indicated by a broken bar (cf. Figure 2).
Membrane composition: 30 wt % PVC, -69 wt % o-NPOE, 1 wt
% ionophore, 70 mol % KTpCiPB. See Experimental Sectlon for the
detailed composition of the background of the three buffers used.
2
1
5
pH OF
AQUEOUS PHASE
4
3
Flgure 4. Fraction a of the protonated ionophore in CDCI, as a
function of the pH of an aqueous phase in equilibrium with the organic
phase. a has been determined on the basis of the I3C chemical shift
of selected carbon atoms of the ionophore (cf. Experimental Section).
The chemical shift for the completely protonated ionophore 11, has
been assessed by adding an equimolar amount of KTpCiPB into the
organic phase and equilibrating it with 4 N hydrochloric acid.
EMF
r
IONOPHORE
KTpClPB
PVC
[mv]
11
/
0.06M Li'
T a b l e I. P h y s i c o c h e m i c a l Properties of
Discussed
the Ionophores
B
1
100 mV
ionophore
1
2
3
4
5
6
7
8
9
10
11
lipophilicity
log PTLC~
-
-31b
36
-43
23.3
16.1
15.7
13.8
15.3
10.8
15.4
15.2
PKC
acronym
10.6
10.6
TDDA
TTDA
THDA
ETH 1548
ETH 595
ETH 1566
ETH 1859
ETH 2043
ETH 2003
ODA
ETH 1778
10.6
9.9
9.3
9.2
7.7
7.1
5.6
4.6
3.6
"Logarithm of the partition coefficient between water and octan-1-01 as determined by thin-layer chromatography (TLC). A
value of 11.6 has been reported in our earlier papers (21,22). More
extensive investigations in the frame of this work revealed that it
is originated in an impurity in the batch of TDDA used at that
time. Dissociation constant of the protonated short-chain homologue of the ionophore (see Experimental Section) in water.
the highly lipophilic ionophores used in this work, the pK
determinations were carried out on short-chain homologues.
I t can be assumed that the basicity of the nitrogen atom of
the carrier involved in the acid/base equilibrium is barely
influenced by an elongation of the alkyl chain. The dynamic
ranges steadily shift to higher p H values as the pK of the
ionophore is increased (Figure 3). The increase of the basicity
of the ionophore leads to an increase in the degree of the
protonation of the ionophore within the membrane at a given
pH of the sample, since the aqueous acid/base equilibrium
(pK) of the ionophore is part of the overall extraction equilibrium
L(m)
+ H+(aq) + X-(as)
LH+(m) + X-(m)
This is confirmed by a determination of the degree of protonation of the ionophore within an organic solvent in equilibrium with an aqueous phase of different pH values by 13C
j,,.,,"
/"
2
o-NPOE
I
,
14
,
,
12
,
,
10
,
,
8
-
,
,
6
,
,
4
,
,
2
,
,
0 pH
-
Figure 5. Influence of the plasticizer used in the membrane on the
1.0 wt % ionophore 11, 1.0 wt
electrode function. Membrane:
% KTpCiPB, -30 wt % PVC, -68 wt % plasticizer as indicated.
Buffer: 60 rnM LiOH, 6.6 mM citric acid, 11.O mM boric acid. The pH
adjustment was done by adding stepwise 4 N hydrochloric acid. The
pH is determined by a pH glass electrode.
NMR (Figure 4). These titration curves shift in the same
way along the pH scale as the potentiometric dynamic ranges
of the corresponding membrane electrodes. The use of CDC13
instead of a solvent polymeric membrane as the organic phase
does not change the relative hydrogen ion extraction significantly (23).
Since different plasticizers extract a given cation to a different extent, the lower detection limit will depend on the
nature of the plasticizer used to form the membrane. Indeed,
Figure 5 shows that TEHP leads to a poor detection limit at
a Li+ background (24),while the use of o-NPOE yields electrodes with a drastically increased dynamic range for the same
cation background. Therefore, membranes based on o-NPOE
will be most suitable candidates for certain sensor applications.
ANALYTICAL CHEMISTRY, VOL. 58, NO. 11, SEPTEMBER 1986
Such sensors are of particular interest in gastrology, where
a dynamic pH range between 0.5 and 7 has to be envisaged
(W).
Yet the electrode shown in Figure 5 satisfies this requirement only partly. Since the selectivity toward Na+ is
poorer than for Li+ (Figure 3, log Kgi = -6.9, log K?;, =
-5.6), the detection limit will strongly depend on the Na+
background found in the gastric sample.
The ionophores presented here have been designed to exhibit a high lipophilicity (see Table I). This is necessary to
cope with the high lipophilic character of biological samples
which will promote the extraction of low molecular weight
components (21).
The rather low electrical resistance of solvent polymeric
membranes (e.g., 2 X lo5 s2 cm for the membrane plasticized
with o-NPOE depicted in Figure 5) as well as the versatility
of the membrane fabrication make a miniaturization of a pH
sensor easily feasible. The applicability of the membrane
system using ionophore 11 in o-NPOE plasticized PVC in a
miniaturized pH sensor for gastroenterological applications
will be reported elsewhere (26).
Preliminary in vitro comparison measurements of electrodes
using this membrane with glass electrodes show a residual
standard deviation of the correlation of 0.15 pH units ( n =
23, pH 0 to 6 sample range). Interestingly, the self-correlation
between two identical polymeric membrane electrodes leads
to a residual standard deviation of 0.02 pH units for the same
sample set. Further work for the elucidation of this behavior
is in progress.
CONCLUSION
Neutral ionophores for hydrogen ion selective membrane
electrodes can be designed by obeying the following points.
The ionophore has to contain a basic nitrogen atom. The pK
of the nitrogen atom will determine the position of the dynamic range of the electrode. A small pK will shift the dynamic range to small pH values and vice versa. For gastrological applications a pK between 4 and 5 seems to be preferable. T o reduce cation interferences, Le., to broaden the
dynamic range, the ionophore should contain neither additional coordination centers as, e.g., amide, ester, or ether
functions, nor structural groups that might form chelate rings
upon coordination with a cation (e.g., ionophore 10). The
choice of a low metal cation extracting membrane solvent has
to be considered with respect to the cation interference as well.
Last, the ionophore should be of high lipophilicity and electrically neutral in the unprotonated form. Therefore, simple
lipophilic, aromatic heterocycles are promising compounds
in this view. Work using such compounds is in progress to
2289
create further improved hydrogen ion ionophores of selected
and wider pH ranges.
ACKNOWLEDGMENT
Samples of gastric juice were obtained and measured in
collaboration with C. Emde and A. L. Blum, Stadtspital
Triemli, Zurich.
LITERATURE CITED
(1) Coon, R. L.; Lai, N. C. J. J. Appi. Physioi. 1978, 4 0 , 625-629.
(2) LeBlanc, 0. H.; Brown, J. F.; Klebe, J. F.; Niederach, L. W.; Slusarczuk, G. M. J.; Stoddard, W. H. J. Appl. fhysiol. 1978, 4 0 , 644-647.
(3) Erne, D.; Ammann, D.; Slmon, W. chimia 1979, 3 3 , 88-90.
(4) Erne, D.; Schenker, K. V.; Ammann, D.; Pretsch, E.; Simon, W. Chimle
1981, 3 5 , 178-179.
(5) Schulthess, P.; Shljo, Y.; Pham, H. V.; Pretsch, E.; Ammann, D.; Simon, W. Anal. Chim. Acta 1981, 131, 111-116.
(6) Ammann, D.; Lanter, F.; Steiner, R. A.; Schulthess, P.; Shijo, Y.; Simon, W. Anal. Chem. 1981, 5 3 , 2267-2269.
(7) Schlue, W. R.; Thomas, R. C. J. Physioi. 1985, 364, 327-338.
(6) Anker, P.; Ammann, D.; Simon, W. Mikrochim. Acta 1983, I ,
237-242.
(9) Opdycke, W. N.; Parks, S. J.; Meyerhoff, M. E. Anal. Chim. Acta
1983, 155, 11-20.
(IO) RuiiEka, J.; Hansen, E. H. Anal. Chim. Act8 1984, 761, 1-25.
(11) Hongbo, C.; Hansen, E. H.; RuiiEka, J. Anal. Chim. Acta 1985, 189,
209-220.
(12) Kessler, M.; Hoper, J.; Volkholz, H.J.; Sailer, D.; Demling, L. Hepatogastroenterology 1984, 3 1 , 285-287.
(13) Funck, R. J. J.; Morf, W. E.; Schuithess, P.; Ammann, D.; Simon, W.
Anal. Chem. 1982, 5 4 , 423-429.
(14) Buchi, R.; Pretsch, E.; Morf, W. E.; Simon, W. Heiv. Chim. Acta 1978,
59,2407-2416.
(15) Oesch, U.;Simon, W. Anal. Chem. 1980, 52,692-700.
(16) Oesch, U.; Brzbzka, 2.; Simon, W., unpubllshed work, 1984.
(17) Oesch, U.;Simon, W., unpublished work, 1986.
(18) Ellgehausen, H.; D'Hondt, Ch.; Fuerer, R. Pestic. Sci. 1981, 12,
219-227.
(19) Handbook of Chemistry and Physics, 56th ed.; CRC Press: Cleveland,
OH, 1975; p D-135.
(20) Guilbault, G. G.; Durst, R. A.; Frant, M. S . ; Freiser, H.; Hansen, E. H.;
Light, T. S.; Pungor, E.; Rechnitz, G.; Rlce, N. M.; Rohm, T. J.; Simon,
W.; Thomas, J. D. R. Pure Appl. Chem. 1976, 4 8 , 127-132.
(21) Oesch, U.; Dinten, 0.; Ammann, D.; Simon, W. Ion Measurements ln
Physiology and Medicine; Kessier, M., Harrison, D. K., Hoper, J., Eds.;
Springer-Verlag: Berlin, Heidelberg, 1985; pp 42-47.
(22) Oesch, U.; Anker, P.; Ammann, D.; Simon, W. Ion-Selective Electrodes; Pungor, E., Buzbs, I., Eds.; Akademiai Kiadb: Budapest, 1985;
pp 81-101.
(23) Erne, D. PhD Thesis ETH 6889, Zurich, 1981.
(24) Oesch, U. Diploma thesis ETH Zurich, Zurich, 1974.
(25) Fimmel, C. J.; Etienne, A.; Cllluffo, T.; Ritter, Ch.; Gasser, Th.; Rey,
J.-P.; Caradonna-Moscateili, P.; Sabbatlni, F.; Pace, F.; Buhler, H. W.;
Bauerfeind, P.; Bium, A. L. Gastroenterology 1985, 8 8 , 1842-1851.
(26) Oesch, U.;Brzbzka, 2.; Xu, A.; Simon, W., submitted for publication in
Med . Bioi. Eng , Comput.
RECE~VED
for review February 26,1986. Accepted May 6,1986.
This work was partly supported by the Swiss National Science
Foundation and by Orion Research, Inc. Z.B. and A.X. thank
the Exchange Service of ETH and the Ministry of Education
of the People's Republic of China, respectively, for grants.