The Ionophores

Fundamentally, ISE operation is largely based on the selective recognition that takes place at the sensing element-sample interface. Before any discussion takes place on this issue, it must be understood that this process is based purely on the second law of thermodynamics, and specifically on the fact that differences in chemical activity between the sensing element and the sample solution tend to even out, assuming that the system is isolated. Based on this requirement, any changes in the activity of the analyte in the test solution must also be distributed evenly in the sensing element membrane. For this to happen there must be selective mass transfer of the analyte from the solution into the membrane, a process that is controlled by the ionophore used. 

An ionophore, from the Greek words ion and/ero (carry), is a compound (organic or organometallic) which can selectively and reversibly coordinate to a specific ion and can thus, based on differences in Gibbs energy, transport the ion from the aqueous solution into a membrane. Up-to-date knowledge in the area of ionophores suggests that there are some very important physicochemical characteristics that a compound must have in order to be a candidate for use as an ionophore in ISEs. The most important of these are  

It is the aim of this chapter is to present the efforts made worldwide for the development of chemical sensors based on the unique chemical recognition capabilities of organotin structures. In particular, we will examine in a time-based flowchart the progress of the design and application of Sn(IV)-based ionophores and their application in the development of anion selective chemical potentiometric sensors. 

4 Organotin-Mediated Anion Partitioning into Liquid Polymeric Membranes 

It was much later, and after the aforementioned work of Rosaro and Kunin, in which it was proven that various synthetic membranes doped with different species could function as ion exchangers, and that these systems were used for quantitative work. Indeed, the properties of these membranes were of 

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Some of these compounds could be considered as dietary additives, but various other terms, including pesticides, can also be used. They can have beneficial effects on the environment and this aspect will be discussed later. The ionophore monensin, which is an alicyclic polyether (Figure 1), is a secondary metabolite of Streptomyces and aids the prevention of coccidiosis in poultry. Monensin is used as a growth promoter in cattle and also to decrease methane production, but it is toxic to equine animals. " Its ability to act as an ionophore is dependent on its cyclic chelating effect on metal ions. ° The hormones bovine somatotropin (BST) and porcine somatotropin (PST), both of which are polypeptides, occur naturally in lactating cattle and pigs, respectively, but can also be produced synthetically using recombinant DNA methods and administered to such animals in order to increase milk yields and lean meat production. "... 

Prince, R., Gnnson, D., and Scarpa, A., 1985. Sdng like a beel The ionophoric properdes of melitdn. Trends in Biochemical Sciences 10 99. 

Thus, it has been shown that calix[4]aryl esters exhibit remarkably high selectivity toward Na [11-14]. This is attributable to the inner size of the ionophoric cavity composed of four 0CH2C=0 groups, which is comparable to the ion size of Na, and to the cone conformation that is firmly constructed on the rigid ca-lix[4]arene platform (Scheme 2). 

Recently, Shinkai and Manabe achieved the active transport of K+ using a new type of carrier 39 derived from diaza crown ether43, 44). The ionophore forms the zwitter-ionic species 39b, which is most lipophilic among other species (39a, 39c), at about neutral pH region, and it acts as effective ion carrier in the active transport... 

Many other cyclic and noncyclic organic carriers with remarkable ion selectivities have been used successfiilly as active hosts of various liquid membrane electrodes. These include the 14-crown-4-ether for lithium (30) 16-crown-5 derivatives for sodium bis-benzo-18-crown-6 ether for cesium the ionophore ETH 1001 [(R,R)-AA -bisd l-ethoxycarbonyl)undecyl-A,yVl-4,5-tctramcthyl-3,6-dioxaoctancdiamide] for calcium the natural macrocyclics nonactin and monensin for ammonia and sodium (31), respectively the ionophore ETH 1117 for magnesium calixarene derivatives for sodium (32) and macrocyclic thioethers for mercury and silver (33). 

Daoud, S. S., and Juliano, R. L. (1986). Reduced toxicity and enhanced antitumor effects in mice of the ionophoric drug valino-mycin when incorporated in liposomes. Cancer Res., 46, 5518-5523. 

Birch and coworkers studied the time-intensity interrelationships for the sweetness of sucrose and thaumatin, and proposed three thematically different processes (see Fig. 47). In mechanism (1), the sweet stimuli approach the ion-channel, triggering site on the taste-cell membrane, where they bind, open the ion-channel (ionophore), and cause a flow of sodium and potassium ions into, or out of, the cell. Such a mechanism would correspond to a single molecular event, and would thus account for both time and intensity of response, the intensity of response being dependent on the ion flux achieved while the stimulus molecule binds to the ionophore. 

The measurement of change in the surface potentials of aqueous solutions of electrolytes caused hy adsorption of ionophore (e.g., crown ether) monolayers seems to he a convenient and promising method to ascertain selectivity and the effective dipole moments of the ionophore-ion complexes created at the water surface. 

The rate of the ion transfer is governed by the complexation reaction, whose rate constant should not depend on potential since it is a purely chemical reaction. However, the concentrations of the reactant change with potential. Typically, the ionophore is uncharged, so that a change in the potential drop affects only the concentration of the ions at the interface. If the thickness X of the interface is neglected, the concentration of the ion at the interface is given by ... 

A composite polymer membrane has also been used as an effective amperometric detector for ion exchange chromatography [42] and showed detection limits similar to those obtained with a conductivity detector. An advantage of the amperometric detector based on micro-ITIES over the conductometric detector is that selectively can be tailored by proper choice of the ionophore. For instance, the selectivity of the membrane toward ammonium in the presence of an excess of sodium could be substantially increased by introducing an ammonium-selective ionophore (such as valinomycin) in the gel membrane [42]. 

FIG. 2 Structures of the ionophores 1-4. 1 =dibenzyl-14-crown4 2 = bis(benzo-15-crown-5) 3 =dibenzo-18-crown-6 4 = dibenzo-24-crown-8 these ionophores are selective for Li+, K+, and Na, respectively. (From Ref 15.)... 

Figure 5 also shows the effect of the ionophore concentration of the Langmuir type binding isotherm. The slope of the isotherm fora membrane with 10 mM of ionophore 1 was roughly three times larger than that with 30 mM of the same ionophore. The binding constant, K, which is inversely proportional to the slope [Eq. (3)], was estimated to be 4.2 and 11.5M for the membranes with 10 mM and 30 mM ionophore 1, respectively. This result supports the validity of the present Langmuir analysis because the binding constant, K, should reflect the availability of the surface sites, the number of which should be proportional to the ionophore concentration, if the ionophore is not surface active itself In addition, the intercept of the isotherm for a membrane with 10 mM of ionophore 1 was nearly equal to that of a membrane with 30 mM ionophore 1 (see Fig. 5). This suggests the formation of a closest-packed surface molecular layer of the SHG active Li -ionophore 1 cation complex, whose surface concentration is nearly equal at both ionophore concentrations. On the other hand, a totally different intercept and very small slope of the isotherm was obtained for a membrane containing only 3 mM of ionophore 1. This indicates an incomplete formation of the closest-packed surface layer of the cation complexes due to a lack of free ionophores at the membrane surface, leading to a kinetic limitation. In this case, the potentiometric response of the membrane toward Li+ was also found to be very weak vide infra).

The sample solution contains a fixed concentration of supporting electrolyte E" L and a varying concentration of primary salt M X . The ionophore I is confined in the membrane. Only the primary cation can be complexed with the ionophore I (given stoichiometry 1 1 stability constant The complex MI and the anionic site are the lipophilic species that are present only in the membrane phase. In this system, the electroneutrality condition at the membrane bulk leads to... 

Next, the complexation equilibrium at the interface must be taken into account. Under the distribution equilibrium of the primary ion between the aqueous and membrane sides of the interface, the complexation reaction between the primary ion and the ionophore occurs at the membrane side of the interface, i.e.. 

Under UV light irradiation, cis-trans photoisomerization of the ionophore in the membrane occurs. We assume that the cis and trans isomers are both present in the membrane and the cis isomer forms a 1 1 (ionophore-cation) complex with a stability constant, Am.cb- In this case, the surface charge density, and the phase boundary... 

Use of ionophore-incorporated membranes leads thus to the same conclusions as described above for the ionophore-free membranes. Here too, the SHG measurements suggest that a permanent, primary ion-dependent charge separation at the liquid-liquid interface, and therefore a potentiometric response, is only possible when the membrane contains ionic sites. 

We recently synthesized several reasonably surface-active crown-ether-based ionophores. This type of ionophore in fact gave Nernstian slopes for corresponding primary ions with its ionophore of one order or less concentrations than the lowest allowable concentrations for Nernstian slopes with conventional counterpart ionophores. Furthermore, the detection limit was relatively improved with increased offset potentials due to the efficient and increased primary ion uptake into the vicinity of the membrane interface by surfactant ionophores selectively located there. These results were again well explained by the derived model essentially based on the Gouy-Chapman theory. Just like other interfacial phenomena, the surface and bulk phase of the ionophore incorporated liquid membrane may naturally be speculated to be more or less different. The SHG results presented here is one of strong evidence indicating that this is in fact true rather than speculation. 

The ionophoric antibiotic nonactin is a 32-membered macrocycle that contains two units of (-)-nonactic acid and two units of (+)-nonactic acid in an alternating sequence. 

The next example, shown in Fig. 4.6a, is the amusing consequence of continually increasing the concentration of background salt (beyond its aqueous solubility—just to make the point) to the shape of log /J/pH profile for acebutolol (whose normal 0.15 M salt curve [362] is indicated by the thick line in Fig. 4.6a). The base-like (cf. Fig. 4.3a) lipophilicity curve shape at low levels of salt can become an acid-like shape (cf. Fig. 4.2a) at high levels of salt An actual example of a dramatic reversal of character is the ionophore monensin, which has a log P (in a background of Na+) 0.5 greater than logP [276,281]. 

Especially sensitive and selective potassium and some other ion-selective electrodes employ special complexing agents in their membranes, termed ionophores (discussed in detail on page 445). These substances, which often have cyclic structures, bind alkali metal ions and some other cations in complexes with widely varying stability constants. The membrane of an ion-selective electrode contains the salt of the determined cation with a hydrophobic anion (usually tetraphenylborate) and excess ionophore, so that the cation is mostly bound in the complex in the membrane. It can readily be demonstrated that the membrane potential obeys Eq. (6.3.3). In the presence of interferents, the selectivity coefficient is given approximately by the ratio of the stability constants of the complexes of the two ions with the ionophore. For the determination of potassium ions in the presence of interfering sodium ions, where the ionophore is the cyclic depsipeptide, valinomycin, the selectivity coefficient is Na+ 10"4, so that this electrode can be used to determine potassium ions in the presence of a 104-fold excess of sodium ions. 

OA Candia, R Montoreano, SM Podos. (1977). Effect of the ionophore A23187 on chloride transport across isolated frog cornea. Am J Physiol 233 F94-F101. 

While ionophore-free membranes based on classical ion exchangers are still in use for the determination of lipophilic ions, such sensors often suffer from insufficient selectivity, as it is governed solely by the lipophilicity pattern of ions, also known for anions as the Hofmeister sequence. This pattern for cations is Cs+ > Ag+ >K+ > NH > Na+ > Li+ > Ca2+ > Mg2+ and for anions CIOT > SCN- > I > Sal- > N03- > Br > N02- > Cl- > OAc- HC03- > SO - > HPO4. While the ion exchanger fixes the concentration of hydrophilic analyte ions in the membrane on the basis of the electroneutrality condition within the membrane, the second key membrane component is the ionophore that selectively binds to the analyte ions. The selectivity of... 

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