Comparison of two molecular design strategies for the development of an ammonium ionophore more highly selective than nonactin

Article abstract of DOI:10.1021/ac025713+

A series of ionophores for ammonium ion-selective electrodes was designed and synthesized, and their characteristics were examined. The design of the ionophores is based on two different strategies: (1) introduction of bulky blocking subunits (decalino gr

Full text of DOI:10.1021/ac025713+

Anal. Chem. 2002, 74, 4845-4848
Comparison of Two Molecular Design Strategies
for the Development of an Ammonium Ionophore
More Highly Selective than Nonactin
Shin-ichi Sasaki,† Tsuyoshi Amano,† Gou Monma,† Takeshi Otsuka,† Naoko Iwasawa,‡
Daniel Citterio,‡ Hideaki Hisamoto,†,§ and Koji Suzuki*,†,‡
Department of Applied Chemistry, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan, and Kanagawa
Academy of Science and Technology (KAST), KSP West-614, 3-2-1 Sakato, Kawasaki 213-0012, Japan
A series of ionophores for ammonium ion-selective elec-
trodes was designed and synthesized, and their charac-
teristics were examined. The design of the ionophores is
based on two different strategies: (1) introduction of bulky
blocking subunits (decalino groups) in 2 0 - or 2 1 -
membered crown ethers (TD20 C6 and TD2 1 C6 ), the ring
+
size of which is expected to be suitable for selective NH4
recognition, as compared to the slightly smaller K+; and
(2 ) preorganized tripodal ionophores based on a 6 -fold
Figure 1. Chemical structures of nonactin (a natural product that
substituted benzene ring in order to complementarily
is known as an ammonium ionophore) and TD19C6 (a synthetic
recognize the tetrahedral NH4 +, in contrast to the spheri-
ionophore that has a 19-membered crown ether with bulky subunits).
cal K+. Compared to nonactin, a natural product that is
+
used as a representative NH4 ionophore, the newly
NH4+/ Na+ selectivity while retaining the NH4+/ K+ selectivity
+
developed TD2 0 C6 showed higher NH4 selectivity over
pot
NH4 ,K
comparable to that of nonactin.2 The design principle of TD19C6
is based on the combination of two factors, namely, the ring size
of the crown ether suitable for the target cation (NH4+) and the
introduction of the bulky blocking subunits to interfere with the
complexation of other cations. A similar principle of molecular
design based on a tetramethylethano subunit was successfully
used in the development of Li+ and Na+ ionophores,3,4 but in the
case of TD19C6, the NH4+/ K+ selectivity was not improved
K+ while retaining the selectivity over Na+ (log
K
)
+
+
pot
-1 .5 and log
K
) -2 .5 ). On the other hand, a
+
+
NH4 ,Na
+
tripodal ionophore with pyrazole nitrogen atoms as NH4
binding sites showed high NH4 +/ K+ selectivity but suf-
pot
NH4 ,K
fered from increased Ca2 + interference (log
K
)
+
+
pot
-2 .1 and log
K
) -1 .6 ). As an overall conclu-
NH4 ,Ca2+
+
sion, the cyclic ionophores TD1 9 C6 and TD2 0 C6 are the
best ammonium-selective ionophores developed to date.
+
because of the similar ionic diameter of NH4 and K+. On the
+
other hand, Chin et al. focused on the different symmetry of NH4
Because of their application to chemical sensors in the field
of clinical or environmental analysis, the design and synthesis of
ammonium ionophores has received much attention during the
last two decades.1,2 Nonactin, a natural product shown in Figure
1, is the only available practically used ammonium ionophore at
and K+ for the design of an ionophore and were successful in
pot
high NH4 selectivity over K+ (log
K
) -2.6). However,
NH4 ,K
+
+
+
the developed ionophore still shows problems, such as low
sensitivity or strong pH dependence.5 Thiazole-containing benzo-
crown ethers6 or cage-type compounds7 have also been reported
as ammonium ionophores, and their characteristics have been
shown to be comparable or even superior to that of nonactin. In
this work, we designed and synthesized eight ionophores on the
+
present. However, the NH4 selectivity of nonactin over K+ or
Na+ is not perfectly sufficient for practical use, and the develop-
ment of a more highly selective ammonium ionophore as ion-
sensing component for ammonium ion-selective electrodes has
been desired. Recently, we developed a 19-membered crown ether
derivative (TD19C6) shown in Figure 1 and realized an excellent
+
basis of two different strategies for NH4 recognition and
(3) Suzuki, K.; Yamada, H.; Sato, K.; Watanabe, K.; Hisamoto, H.; Tobe, Y.;
Kobiro, K. Anal. Chem. 1 9 9 3 , 65, 3404.
(4) Suzuki, K.; Sato, K.; Hisamoto, H.; Siswanta, D.; Hayashi, K.; Kasahara, N.;
Watanabe, K.; Yamamoto, N.; Sasakura, H. Anal. Chem. 1 9 9 6 , 68, 208.
(5) Chin, J.; Walsdorff, C.; Stranix, B.; Oh, J.; Chung, H. J.; Park, S.-M.; Kim,
K. Angew. Chem., Int. Ed. Engl. 1 9 9 9 , 38, 2756.
(6) Kim, H.-S.; Park, H. J.; Oh, H. J.; Koh, Y. K.; Choi, J.-H.; Lee, D.-H.; Cha,
G. S.; Nam, H. Anal. Chem. 2 0 0 0 , 72, 4683.
(7) Jon, S. Y.; Kim, J.; Kim, M.; Park, S.-H.; Jeon, W. S.; Heo, J.; Kim, K. Angew.
Chem., Int. Ed. 2 0 0 1 , 40, 2116.
* To whom correspondence should be addressed. Tel: +81-45-566-1568.
Fax: +81-45-564-5095. E-mail: suzuki@applc.keio.ac.jp.
† Keio University.
‡ Kanagawa Academy of Science and Technology.
§ Present address: Department of Applied Chemistry, Graduate School of
Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8566.
(1) Bu¨ hlmann, P.; Bakker, E.; Pretch, E. Chem. Rev. 1 9 9 8 , 98, 1593.
(2) Suzuki, K.; Siswanta, D.; Otsuka, T.; Amano, T.; Ikeda, T.; Hisamoto, H.;
Yoshihara, R.; Ohba, S. Anal. Chem. 2 0 00 , 72, 2200 and references therein.
10.1021/ac025713+ CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/10/2002
Analytical Chemistry, Vol. 74, No. 18, September 15, 2002 4845

Figure 2. Schematic representation of the two approaches to the development of ammonium ionophores: (a) rigid crown ethers having a
+
suitable diameter for NH4+ with bulky blocking subunits and (b) preorganized tripodal ionophores complementarily recognizing tetrahedral NH4
with three binding sites.
examined their characteristics as ammonium ionophores for ion-
selective electrodes.
separate-solution method (SSM; [I] ) [J] ) 0.1 M) according to
the recommendations of IUPAC and JIS.9-11
RESULTS AND DISCUSSION
EXPERIMENTAL SECTION
+
To recognize NH4 selectively, two kinds of ionophore mol-
Reagents. The highest grade commercially available reagents
were used for the preparation of the aqueous test electrolytes.
The distilled and deionized water used had a resistivity of greater
than 1.5 × 107 Ω cm at 25 °C. The electrode membrane solvent
bis(1-butylpentyl) adipate (BBPA) was purchased from Fluka AG,
Buchs, Switzerland. Poly(vinyl chloride) (PVC, high-molecular-
weight type) used as the electrode membrane material was
obtained from Sigma, Chemical Co. (St. Louis, MO). Synthetic
procedures for ionophores are described in the Supporting
Information.
ecules were designed and synthesized as illustrated in Figure 2.
The first concept of the molecular design uses cyclic crown ethers
combined with three Decalino groups. This bulky subunit is
known to act not only as a “block wall” in order to hinder the
formation of sandwich-type complexes with larger cations but also
as the origin of rigidity of the crown ether ring to prevent the
formation of wrapping-type complexes with smaller cations.
Furthermore, Decalino groups are desirable to increase the
lipophilicity of the ionophore molecules, which is an important
factor in view of the practical application.2 Because the 19-
membered crown ether (TD19C6) based on this approach showed
almost the same NH4+/ K+ selectivity as that of nonactin, 20- and
21-membered crown ethers were selected to reduce the interfer-
ence of the smaller K+ ion.
The second concept is based on the tridimensional shape of
the ionophores. Preorganized noncyclic tripodal ionophores based
on a 6-fold substituted benzene ring as a spacer unit were
selected,12 since several receptors/ ionophores have recently been
developed for cation or anion recognition using this kind of
approach.5,13-18 To distinguish the tetrahedral NH4+ from spherical
cations complementarily, a series of binding units was introduced
into this tripodal unit. In addition to the conformational effect, a
The lipophilicity (log PO/ W, the octanol-water partition coef-
ficient) of the ionophores was measured according to a previously
reported procedure.8
Electrode P reparation and emf Measurements. The PVC
matrix-based membranes were prepared from a mixture composed
of 3 wt % ionophore, 67 wt % BBPA, 30 wt % PVC, and 10 mol %
(relative to the ionophore) anionic additive (KTCPB) for crown
ethers and 25 mol % NaTFPB for tripodal ionophores KTA-1-
KTA-5. The cocktail components dissolved in THF were poured
into a vial and put on a hot plate. Slow evaporation of THF at 40
°C gave ion-selective membranes of ∼100-µm thickness. A 6-mm-
diameter circle was cut from a prepared membrane and placed
on the tip of a PVC ion-selective electrode body assembly (Liquid
Electrode Membrane Kit, DKK Co., Ltd., Tokyo, Japan). The
prepared electrodes were immersed in 0.1 M aqueous NH4Cl
solution for more than 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 potential (emf) measurements were performed at 25 (
0.5 °C using the electrochemical cell system, Ag |AgCl| saturated
KCl |0.3 M NH4NO3 ||sample solution |ISE membrane |0.1 M
NH4Cl| AgCl|Ag.
+
cation-π interaction is also expected in the case of NH4
binding.7,19 Although ethyl groups seem to be sufficient to show
(9) IUPAC Recommendations for Nomenclature of Ion-Selective Electrodes,
Pure Appl. Chem. 1 9 9 4 , 66, 2527.
(10) IUPAC Selectivity Coefficients for Ion-Selective Electrodes: Recommended
pot
A,B
Methods for Reporting K Values; Pure Appl. Chem. 1 9 9 5 , 67, 507.
(11) JIS K-0122; Japanese Standards Association: Tokyo, 1997.
(12) Iverson, D. J.; Hunter, G.; Blount, J. F.; Damewood, J. R., Jr.; Mislow, K. J.
Am. Chem. Soc. 1 9 8 1 , 103, 6073.
(13) Metzger, A.; Lynch, V. M.; Anslyn, E. V. Angew. Chem., Int. Ed. Engl. 19 97 ,
36, 862.
(14) Cabell, L. A.; Monahan, M.-K.; Anslyn, E. V. Tetrahedron Lett. 1 9 9 9 , 40,
7753.
(15) Schneider, S. E.; O’Neil, S. N.; Anslyn, E. V. J. Am. Chem. Soc. 2 0 0 0 , 122,
542.
(16) Cabell, L. A.; Best, M. D.; Lavigne, J. J.; Schneider, S. E.; Perreault, D. M.;
Monahan, M.-K.; Anslyn, E. V. J. Chem. Soc., Perkin Trans. 2 2 0 0 1 , 315.
(17) Sasaki, S.; Citterio, D.; Ozawa, S.; Suzuki, K. J. Chem. Soc., Perkin Trans. 2
2 0 0 1 , 2309.
(18) Sasaki, S.; Ozawa, S.; Citterio, D.; Iwasawa, N.; Suzuki, K. Anal. Sci. 2 0 0 1 ,
17 (supplement), i1659.
All sample solutions were prepared from the chloride salts of
each cation without any pH-adjusting buffer reagent, except in
the case of the electrode based on KTA-1, in which 0.1 M Tris-
HCl buffer adjusted to pH 7.2 was used. The selectivity coefficients
pot
I,J
K
, where I stands for the primary ion (NH4+) and J for the
interfering ion, were calculated from the response potentials in
an alkali metal or alkaline earth metal chloride solution using the
(8) Dinten, O.; Spichiger, U. E.; Chaniotakis, N.; Gehrig, P.; Rusterholz, B.;
(19) Oh, K. S.; Lee, C.-W.; Choi, H. S.; Lee, S. J.; Kim, K. S. Org. Lett. 2 0 0 0 , 2,
2679.
Morf, W. E.; Simon, W. Anal. Chem. 1 9 9 1 , 63, 596.
4846 Analytical Chemistry, Vol. 74, No. 18, September 15, 2002

Figure 4. EMF response curves of the electrodes based on
TD19C6, TD20C6, and TD21C6, which have 19-, 20-, and 21-
membered crown ethers with three blocking subunits, respectively.
Figure 3. Chemical structures of the newly synthesized ammonium
ionophores.
a preorganization effect, the longer butyl groups were chosen to
increase the lipophilicity of the ionophores. As binding sites,
nitrogen atoms of pyrazole rings, oxygen atoms of phenolic ethers,
and oxygen atoms of amide carbonyl groups were selected for
investigation. Thus, the two crown ethers TD20C6 and TD21C6,
and the tripodal ionophores KTA-1 to KTA-5 shown in Figure 3
were newly designed and synthesized.
Figure 5. Potentiometric selectivity coefficients of the ISEs based
on TD19C6, TD20C6, TD21C6, and nonactin.
The lipophilicity parameters (log PO/ W) of TD20C6 and TD21C6
are 14.6 and 15.2, respectively, which are higher than that of
TD19C6 (13.5) as a result of the increase in the ratio of carbon to
oxygen atoms, and these values are much superior to that of
nonactin (5.8). The characteristics of the electrodes based on
TD20C6 and TD21C6 were examined on the basis of the optimized
condition for TD19C6 (see Experimental Section). As shown in
Figure 4, these ionophores showed theoretical Nernstian response
over a wide concentration range and a good detection limit lower
than 1 × 10-5 M. The electrode response slopes were 59.3 and
59.1 mV/ decade for TD20C6 and TD21C6, respectively. The
selectivity coefficients of the NH4+ electrodes based on TD19C6,
TD20C6, TD21C6, and nonactin are shown in Figure 5. Although
every electrode shows good NH4+ selectivity, it should be pointed
Figure 6. Potentiometric selectivity coefficients of the tripodal
ionophores KTA-1, KTA-2, KTA-3, KTA-4, KTA-5, and nonactin.
out that TD20C6 and TD21C6 have higher NH4+/ K+ selectivity
pot
NH4 ,K
(log
K
) -1.5 and -1.6, respectively), as compared to
6. Among the five ionophores examined, only KTA-1 showed high
+
+
pot
NH4 ,K
+
those of TD19C6 (-1.0) and nonactin (-1.0). Because the crown
rings become more flexible as the ring size is increased, the
interference of small cations, such as Li+, Na+, or Ca2+, is
increased in the order of TD19C6 < TD20C6 < TD21C6, probably
as a result of the formation of wrapping-type complexes. However,
the NH4+/ Na+ selectivity of TD20C6 is still comparable to that of
nonactin. Therefore, it is concluded that the characteristics of
NH4 selectivity, especially over K+ (log
K
selectivity,
+
+
-2.1), although the sensitivity is not as good as reported for a
similar ionophore in the literature (detection limit, 1 × 10-3 M)5,
and it was found that the interference of Ca2+ is serious. The
selectivity of the ether-type ionophores KTA-2 and KTA-3 is quite
different, which is caused by the length of the methylene unit
connecting the binding sites and the spacer benzene ring. KTA-2
+
+ 20
TD20C6 as NH4 ionophore are superior to those of nonactin in
shows no selectivity for NH4
,
and extremely poor selectivity
+
view of practical use.
On the other hand, the selectivity coefficients of the electrodes
based on tripodal ionophores KTA-1-KTA-5 are shown in Figure
was observed for NH4 over alkali cations in the case of KTA-3.
The amide-type ionophore KTA-4 showed a limited NH4+ selectiv-
ity, but it is far from that of nonactin. Moreover, an increase
Analytical Chemistry, Vol. 74, No. 18, September 15, 2002 4847

in the Ca2+ interference is observed in the case of KTA-4 and
KTA-5.
SUPPORTING INFORMATION AVAILABLE
Supporting Information Available: Detailed synthetic proce-
dures for ionophores. This material is available free of charge via
the Internet at http:/ / pubs.acs.org.
In conclusion, the strategy based on the rationally designed
crown ether showed better results in the development of novel
ammonium ionophores. Among the newly synthesized ionophores,
TD20C6 possessing a 20-membered crown ring and three Deca-
lino groups is the best ammonium ionophore developed to date.
In addition, 19-membered TD19C6 is also an excellent ammonium
ionophore as a result of its high NH4+/ Na+ selectivity.
ACKNOWLEDGMENT
Support of this investigation was provided in part by the
Kanagawa Academy of Science and Technology and the Ministry
of Science and Technology. This study was also supported in part
by a Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports and Culture. D.C. gratefully acknowl-
edges a research fellowship granted by the Science and Technol-
ogy Agency of Japan (STA).
(20) 1,3,5-Triethyl-2,4,6-tris(2-methoxyphenyloxymethyl)benzene, which has a
structure similar to KTA-2, is reported to have NH4 selectivity over K+
+
and Na+. However, even under the reported membrane and measurement
conditions (ref 7, Supporting Information), the selectivity pattern for KTA-2
was not improved significantlly. Therefore, the observed lower selectivity
might be attributed to a sterical effect of the butoxy groups in KTA-2.
Received for review April 15, 2002. Accepted July 3, 2002.
AC025713+
4848 Analytical Chemistry, Vol. 74, No. 18, September 15, 2002