liquid/liquid interfaces, electrochemistry at

Liquid/Liquid Interfaces,Electrochemistry at

Pekka PeljoAalto University, Espoo, Finland

Hubert H. GiraultEcole Polytechnique Federale de Lausanne,Lausanne, Switzerland

1 Introduction 12 Theoretical Background 2

2.1 Thermodynamics for the Partition ofIons 2

2.2 Structure of the Interface and PotentialDistribution 4

2.3 Charge-Transfer Reactions 43 Experimental Set-up 54 Analytical Methods 6

4.1 Cyclic Voltammetry 64.2 Hydrodynamic Methods 74.3 Micro- and Nanointerfaces Between

Two Immiscible Electrolyte Solutions 74.4 Three-phase Electrodes 104.5 Spectroscopic Techniques 104.6 Scanning Electrochemical Microscopy 11

5 Applications 125.1 Amperometric Ion Sensors and

Detectors 125.2 Macromolecule Sensing at

Liquid/Liquid Interface 135.3 Analytical Aspects of Metal Extraction 145.4 Electrochemistry of Drugs at

Liquid/Liquid Interfaces 156 Conclusion 17

Acknowledgment 17Abbreviations and Acronyms 17List of Symbols 18Related Articles 18References 18

Update based on the original article by Frederic Reymond, HubertH. Girault, Encyclopedia of Analytical Chemistry,© 2000, John Wiley &Sons, Ltd

This article outlines the electrochemical methodologyat the interface between two immiscible electrolytesolutions (ITIES). The fundamental concepts of thethermodynamics in biphasic systems are presented in orderto show how ions are distributed between the two adjacentphases and hence, how a Galvani potential difference isestablished at an ITIES. Polarizable and nonpolarizableITIES are then characterized, and it is further evidencedthat the classical electroanalytical methodology at a solidelectrode can be directly transposed to the ITIES, therebyallowing reversible charge-transfer reactions to be easilymonitored and interpreted.

This theoretical approach is completed by a reviewof the analytical methods used at ITIES, namely cyclicvoltammetry (CV), hydrodynamic methods, spectroscopictechniques, and micro- and nanointerfaces (which arethe biphasic analogs of micro- and nanoelectrodes).The last part deals with the practical applicationsthat electrochemistry at ITIES has attracted duringthe past decades in the development of amperometricand coulometric ion sensors and detectors, detection ofmacromolecules, extraction of metal ions by interfacialformation of a complex, and assessment of the propertiesand lipophilicity of ionizable drugs.

1 INTRODUCTION

Electrochemistry at the ITIES is concerned with threemain types of charge-transfer reactions, namely,

• ion-transfer (IT) reactions from one phase to another;• IT reactions assisted by the presence of a complexing

agent;• electron-transfer (ET) reactions between a hydro-

philic and a hydrophobic redox couple.

So far, the electroanalytical applications of electro-chemistry at liquid/liquid interfaces have been limited tosimple or assisted ITs,(1) and this article is restricted tothis subject.

The amperometric study of IT reactions is a relativelyrecent area that was developed in the 1970s in France byGavach et al.(2 – 5) and in Prague by Koryta et al.(6 – 10) whodemonstrated that the ITIES were polarizable in the sameway as the interface between a metallic electrode and anelectrolyte solution. It ensued that techniques commonlyused for the measurement of ET at solid/liquid interfacescould be applied to study transfer processes through theITIES.

The route to modern studies of the interfacial structureof both the ITIES and charge-transfer reactions startedonly with the introduction of the concept of the four-electrode potentiostat with ohmic drop compensation,(6)

Encyclopedia of Analytical Chemistry, Online © 2006–2012 John Wiley & Sons, Ltd.This article is © 2012 John Wiley & Sons, Ltd.This article was published in the Encyclopedia of Analytical Chemistry in 2012 by John Wiley & Sons, Ltd.DOI: 10.1002/9780470027318.a5306.pub2

© 2012 John Wiley & Sons. Reprinted by permission of John Wiley & Sons.

2 ELECTROANALYTICAL METHODS

which permitted potentiostatic control of the interfacialpotential difference. Most publications have reportedmainly the experimental results as summarized inreviews,(11 – 13) and in comparison, few theoretical modelsof charge-transfer processes and the interfacial structurehave been proposed, as described in the recent reviewsby Dryfe(14) and Samec.(15) Although the potentialdistribution at the ITIES is now well established,(16) thestructure of the interface and the kinetics of transfer arestill controversial subjects.(14,17)

Numerous efforts have been made to reach a betterunderstanding of the molecular mechanisms involved inionic motion in liquids,(1,14,18) and results suggest thatthe rate-limiting step in ion transport is the necessaryinterchange of the solvation shell from one liquid tothe other. The roughness of the interface is likely tomanifest itself as capillaries or fingers of one liquidprotruding into another.(19,20) This ‘fingering’ resultingfrom the long-range ion–dipole interactions plays a majorrole in the change of the solvation shell,(21) implyingthat IT may be an activated process.(22) This has beencorroborated by molecular dynamics calculations,(21,23)

which tend to confirm that the interface is sharp at themolecular level but in average, can be considered as anextended region in which the two solvents mix. One of thegreatest challenges in the theory of ITIES is to understandthe spatial distribution of the driving forces. From anelectroanalytical viewpoint, the majority of the charge-transfer reactions studied are reversible (i.e. kineticallyfast) and the development of their applications is nothindered by these theoretical limitations.

This article is intended to describe the general theory ofcharge-transfer reactions at ITIES and outline the variousmethodologies that electrochemistry at liquid/liquidinterfaces offers for analytical purposes. It does not dealwith interfacial structure and kinetics, which have beenthoroughly discussed in a recent review,(14) but focuseson the various applications of ITIES and on recentadvances in this field. Also, the very important field of theion-selective electrode (ISE),(24,25) which is a significantapplication of electrochemistry at liquid/liquid interfacesis discussed only briefly, as it is a subject of its own.

2 THEORETICAL BACKGROUND

2.1 Thermodynamics for the Partition of Ions

2.1.1 Gibbs Energy of Transfer and Nernst Equation atthe Interface Between Two Immiscible ElectrolyteSolutions

The standard transfer Gibbs energy of a species fromone phase (say water) to another phase (say the organic

solvent), �Go,w→ot , is by definition equal to the difference

between the standard Gibbs energy of solvation, μo,o,and the standard Gibbs energy of hydration, μo,w

(Equation 1).

�Go,w→ot = μo,o − μo,w (1)

In the case of an ionic species i, we have to consider theelectrochemical potentials that are equal at equilibrium.In developing this equality, we can write Equation (2) as

μo,wi + RT ln aw

i + ziFφw = μo,oi + RT ln ao

i + ziFφo (2)

from which we can express the Galvani potentialdifference between the two phases �w

o φ according toEquation (3) as

�wo φ = �w

o φoi + RT

ziFln

(ao

i

awi

)= �w

o φo′i + RT

ziFln

coi

cwi

(3)

where ai and ci are the activity and the concentration ofthe ion, respectively, in both phases and �w

o φoi and �w

o φo′i

are called the standard and the formal transfer potentials,respectively.

This equation is often called the Nernst equation for ITat liquid/liquid interfaces, and the term �w

o φoi corresponds

to the standard Gibbs energy of transfer expressed on avoltage scale (Equation 4):

�wo φo

i = �Go,w→ot,i

ziF(4)

It is important to realize that although the Nernstequation for IT resembles the classical Nernst equationfor redox reactions at an electrode, there is no redoxreaction involved in the definition of Equation (3).

If a ligand or an ionophore able to complex thetransferring ion is present in the organic phase thenthe complexation equilibrium can be taken into account.In the case of 1:1 stoichiometry, the association constantis simply given by Equation (5):

Ka = aoML

aoMao

L(5)

where M refers to the transferring ion and L to the ligand.The Galvani potential difference now reads as Equation(6):

�wo φ = �w

o φoM + RT

zMFln

(ao

M

awM

)

= �wo φo

ML + RT

zMFln

(ao

ML

awM

)(6)


LIQUID/LIQUID INTERFACES, ELECTROCHEMISTRY AT 3

with the apparent standard transfer potential given byEquation (7):

�wo φo

ML = �wo φo

M − RT

zMFln(Kaa

oL) (7)

This equation shows that the presence of an ionophorein the organic phase can shift the apparent solvationenergy and, therefore, facilitate the transfer of hydrophilicspecies from water to oil. We shall call this type of ITreaction facilitated ion transfer (FIT). An important classof such reactions is the interfacial acid–base reactions inwhich, for example, a lipophilic base binds an aqueousproton at the interface to transfer it to the organic phase.

2.1.2 Polarizable and Nonpolarizable InterfaceBetween Two Immiscible Electrolyte Solutions

If a salt such as tetrabutylammonium bromide is dissolvedin two immiscible solvents in contact, the distributionof the salt induces a polarization of the interface. Theresulting Galvani potential difference is then called adistribution potential and is defined by applying Equation(3) to both the cation and the anion (Equation 8):

�wo φ = �w

o φo+ + RT

Fln

(ao+aw+

)= �w

o φo− − RT

Fln

(ao−aw−

)

(8)

In the case of dilute solutions, this equation simplifiesto Equation (9):

�wo φ = 1

2(�w

o φo+ + �w

o φo−) (9)

This simple example illustrates that as soon as wepartition salts between two adjacent phases, the interfacebecomes polarized at a fixed potential defined by thestandard transfer potentials of the different ionic species.Because this polarization potential is fixed, we shall saythat the interface is nonpolarizable in the sense that it isnot possible to polarize the interface without modifyingthe chemical composition of the two phases.

In the case where a hydrophilic salt is dissolved in waterand a hydrophobic salt is dissolved in the organic phasesuch that the concentration of the hydrophilic salt in theorganic phase is negligible compared with that of thehydrophobic salt and, conversely, the concentration ofthe hydrophobic salt in water is negligible compared withthat of the hydrophilic salt, the interface will be calledpolarizable. This definition means that it is now possibleto polarize the interface from an external potentialsource without modifying the chemical composition ofthe adjacent phases. In this way, there is what is calleda potential window such that it is possible to polarize

the interface up to a point where the applied Galvanipotential difference is enough for an ion to transfer.

To illustrate the principle of the potential window, letus consider an interface between an aqueous solution ofLi2SO4 and a solution of tetrabutylammonium (TBA+)and tetraphenylborate (TPB−) in an organic solvent,e.g. 1,2-dichloroethane (1,2-DCE). At the potential ofzero charge, the two adjacent phases are by definitionuncharged. If a positive Galvani potential difference(water vs oil) is applied from an external source, two back-to-back Gouy–Chapman diffuse layers will be establishedwith an excess of cations in the aqueous phase andan excess of anions in the organic phase.(18,26,27) Asshown in Figure 1, we can polarize the interface untilthe Galvani potential difference reaches the standardtransfer potential of either Li+ or TPB−. As it happens,the standard transfer potential of TPB− is less than thatof Li+ (�w

o φoTPB− = 340 mV and �w

o φo

Li+ = 580 mV), andTPB− then starts to transfer as soon as the Galvanipotential difference approaches 200 mV. The chemicalcomposition of the adjacent phases is then altered bythe Faradaic current across the interface and the redoxreactions at the two electrodes connected to the externalsource. If instead of using TPB− as the organic anionwe choose a more hydrophobic anion such as tetrakis(4-chlorophenyl)borate (TPBCl−) for which the standardtransfer potential is very large, then a positive polarizationof the interface will result in the transfer of Li+ from waterto oil (Figure 1). It can be concluded that TPBCl− is morehydrophobic than Li+ is hydrophilic.

When a negative polarization is applied then the inter-face is polarized until the Galvani potential differencereaches the standard transfer potential of either TBA+ orSO4

2− (�wo φo

TBA+ = −230 mV and �wo φo

SO2−4

< −600 mV,

respectively). Since the standard transfer potential ofSO4

2− is more negative than that of TBA+, the potential

TPB−

TBA+

Li+

−0.4 −0.3 −0.2 0.1 0.2 0.3 0.4 0.5−0.1

−20

−40

40

20

0

SO42−

Cur

rent

den

sity

(mA

cm

−1)

0

Δο φ (V)W

Figure 1 Potential window for 1,2-DCE/water systemscontaining 5 mM Li2SO4 as aqueous supporting elec-trolyte and 5 mM tetrabutylammonium tetraphenylborate(TBATPB) or 5 mM bis(triphenylphosphoranylidene) ammo-nium tetrakis(4-chlorophenyl borate) (BATPBCl) as organicsupporting electrolyte.



window is limited by the transfer of TBA+. However, if weuse in the organic phase a more hydrophobic cation suchas bis(triphenylphosphoranylidene) ammonium (BA+),which has a very negative standard transfer potential,then the potential window is limited by the transfer ofSO4

2−. Again, it can be concluded that BA+ is morehydrophobic and sulfate is hydrophilic. Standard Gibbsenergies of IT have been tabulated in different reviewsand in a database.(11,28 – 31)

2.2 Structure of the Interface and PotentialDistribution

The structure of the liquid–liquid interface has beenthoroughly discussed in the recent review by Dryfe,(14)

so a detailed discussion is omitted here. A liquid/liquidinterface is by definition a molecular interface betweentwo condensed media. The solvent dynamics results inan interface fluctuating to a certain limit following thecapillary wave theory. If we take a time average view ofthe interface, we can say that it is composed of a thinmixed solvent layer, with a thickness of ca. 10 A based onmolecular dynamics simulations and neutron reflectivityexperiments.(32) Snapshots from molecular dynamicscomputer simulation show that the local structure ofthe interface is greatly influenced by the presence of ioniccharges.(14)

The distribution of ions at an electrified ITIEShas been recently determined by X-ray reflectivityat the water/nitrobenzene (NB)(33,34) and water/1,2-DCE interface,(35) showing clearly the failure ofGouy–Chapman theory at large Galvani potentialdifferences perhaps indicating that the interface becomesless ideally polarized. Instead, an ion-specific Poisson–Boltzmann equation incorporating a potential of meanforce for each ion to account for the variation of solvationin the interfacial region agreed excellently with theexperimental results.

2.3 Charge-Transfer Reactions

2.3.1 Simple Ion Transfer

From a practical viewpoint, the kinetics of IT can beconsidered as very fast, such that it can be assumedthat the surface concentrations always follow the Nernstequation (Equation 3). In electrochemical nomenclature,it is then said that IT reactions are reversible. Similarly, toa reversible redox reaction on an electrode that is limitedby the mass transfer of the reactants to the electrodeand by that of the products away from the electrode,an IT reaction is limited by the mass transfer of ions tothe interface and away from it. Hence, the mass transportdifferential equations and boundary conditions are similar

in both cases, and all the electroanalytical methodologycan, therefore, be transposed to the study of IT reactions.

As in classical amperometry, the response of the systemstems from the resolution of the diffusion equations ofthe ion in the two adjacent phases (Equation 10):

∂cwi

∂t= Dw

i∂2cw

i

∂x2and

∂coi

∂t= Do

i∂2co

i

∂x2(10)

By taking the interface as the origin, the current is thensimply given by the flux of species i across the interfaceof area A (Equation 11):

I = ziFA

(∂cw

i

∂x

)x=0

(11)

The boundary conditions are the Nernst equation(Equation 3) and the equality of the fluxes (Equation 12),when distance from the interface is defined positive in theaqueous phase and negative in the oil phase.

Dwi

(∂cw

i

∂x

)x=0

− Doi

(∂co

i

∂x

)x=0

= 0 (12)

The problem can be solved analogously to the classicalamperometry at solid electrode.(36) If the transferringspecies i is initially present only in the aqueous phase(Equation 13) and semi-infinite conditions are taken forthe boundaries far from the interface (Equation 14)

cwi (x, 0) = c

w,∗i ; co

i (x, 0) = 0 (13)

limx→∞ cw

i (x, t) = cw,∗i ; lim

x→−∞ coi (x, t) = 0 (14)

The problem can be solved by application of Laplacetransform to yield

I = ziFADw1/2

i cw,∗i

π1/2t1/2(1 + ξθ)(15)

where ξ =(

Dwi

Doi

) 12

and θ = cwi

coi

= exp[

zF

RT(�w

o φ − �wo φo

i )

]

(reformulation of Nernst equation (Equation 3).The case for co

i (x, 0) = co,∗i follows analogously.

2.3.2 Facilitated Ion Transfer

Assisted IT reactions are also very fast and canbe considered reversible in most cases. However,mass transport is more complicated, and as shownschematically in Figure 2, we can distinguish four types ofreactions:(37)



Transfer by interfacialcomplexation

Transfer by interfacialdecomplexation

Aqueous complexationfollowed by transfer

Transfer followed byorganic phasecomplexation

Figure 2 Schematic representation of assisted ion-transferreactions.

• aqueous complexation followed by transfer (ACT);• transfer by interfacial complexation (TIC);• transfer by interfacial decomplexation (TID);• transfer followed by organic-phase complexation

(TOC).

In each case, we have to consider the mass transport ofthe ions and the ligands to and away from the interface.This leads to many specific cases that have been treatedin the literature (Section 4.2). More interesting from anelectroanalytical aspect are the two limiting cases whereeither the ions or the ligands are in excess in theirrespective phases. In these two cases, the mass transportis limited by that of the ligand or the ions, respectively.

Assisted, or facilitated, IT was first reported in 1979 byKoryta,(7) who observed that the transfer of potassiumand sodium ions in the aqueous phase was facilitated bythe formation of a complex in the organic phase withthe synthetic polyether dibenzo-18-crown-6 (DB18C6)and with the natural antibiotic valinomycin, respectively.This work was a landmark in ITIES research because itmeant that both potential window-limiting species andneutral ionophore molecules were amenable to study. Asa result, this field spread quickly to solvent extractionand purification, detection of trace ions, assisted transferof proton, and development of amperometric sensors(Section 4).

2.3.3 Photoelectrochemistry at Interface Between TwoImmiscible Electrolyte Solutions

From the early days, liquid–liquid interfaces have beenconsidered as a biomimetic model of biomembranes, andsome work was dedicated to study photoinduced reactionswith the long goal to study artificial photosynthesis. Forexample, Kotov and Kuzmin(38) studied the transfer ofphotogenerated ions. But then, it was quickly realized thatit was possible to study photoinduced electron-transferreactions between an excited sensitizer in one phase anda redox quencher in the adjacent phase. Fermin et al.published a series of papers to characterize the differentsteps of those photoinduced processes (see, for example,part VII(39)). A good level of understanding was reachedas it was even possible to model it analytically.(40) Morerecently, it has been shown that these photoinducedelectron-transfer reactions could be enhanced by thepresence of gold nanoparticles by a surface plasmonresonance effect.(41)

3 EXPERIMENTAL SET-UP

As discussed in Section 2, the interface between twoimmiscible electrolytes can be polarized using an externalsource. From an experimental viewpoint, it is usual tooperate with a four-electrode potentiostat comprisingtwo reference electrodes and two counter electrodes toprovide the current,(6,42) as illustrated in Figure 3. Also,three-electrode configurations are used for the so-calledthree-phase electrodes (Section 4.3), and two-electrodeset-up can be used for microinterfaces (Section 4.2).

Different solvents, most commonly NB, 1,2-DCE,and o-nitrophenyl octyl ether (NPOE), have been usedto study charge-transfer reactions, and most of themare either expensive or toxic. The solvents and thesystems studied at ITIES have been listed in recentreviews.(12,13) Very recently, Olaya et al.(43) have shownthat trifluorotoluene is a good solvent immiscible withwater, with a reasonably high dielectric constant and notas toxic as 1,2-DCE.

As described in Section 2, the potential window islimited by the supporting electrolytes. It is desirableto have as wide as possible potential window. Hence,TBATPB traditionally used in the oil phase has beenreplaced by more hydrophobic salts, such as bis(triphenyl-phosporanylidene) ammonium tetrakis(pentafluoro-phenyl) borate (BATB). This supporting electrolyte ishydrophobic enough that the potential window is limitedby the transfer of species in the aqueous phase. Typi-cally, the organic supporting electrolytes are preparedby the metathesis of stoichiometric amounts of chlorideand lithium salts of the ions (for example, BACl and



CE (o)

CE (w)

Ref. (w) Ref. (o)

Figure 3 Schematic diagram of an electrochemical cell for thestudy of charge-transfer reactions at an ITIES. For the systemin Figure 1, the aqueous reference electrode can be Ag|Ag2SO4. The organic reference electrode includes an unpolarizedliquid junction using the organic cation or anion as the commonion. If the organic supporting electrolyte is TBATPB, the liquidjunction can comprise either tetrabutyl ammonium chloride(TBACl) or sodium tetrabutylborate (NaTPB) so that thereference electrode can be TBATPBo|TBAClw|AgCl|Ag orTBATPBo|NaTPB|AgTPB|Ag.

LiTB) dissolved in 2:1 mixture of methanol and water.The precipitate is recrystallized from acetone and washedwith the 2:1 mixture of methanol and water to remove thestarting materials.

Another recent development has been to use roomtemperature ionic liquids (RTILs), as described inrecent reviews.(44 – 46) The advantages of RTILs includenegligible volatility, reasonable conductivity, and uniquesolvation properties. However, they suffer from highviscosity, leading to lower mass transport rate. Thewidth of the potential window depends on the solubilityof the ionic liquid in water. By a choice of suitableions, a potential window comparable to the w/1,2-DCEsystem has been achieved. The investigation of w/RTILsystems also led to a discovery of a conceptually newsalt bridge based on moderately hydrophobic RTIL thatis able to form a stable junction potential in conditionswhere KCl-type salt bridges have major shortcomings.These RTIL-based salt bridges offer a simple and anaccurate way to estimate single ion activities, mostnotably pH. These salt bridges still suffer from thepartition of hydrophobic ions in the sample solution,but careful choice of ionic liquid can diminish theinterference.(46)

4 ANALYTICAL METHODS

4.1 Cyclic Voltammetry

Cyclic voltammograms produced by reversible IT reac-tions are similar to those obtained for reversible ETreactions at a metal/electrolyte solution interface,(47) asshown in Figure 4. Thus, for reversible transfer reactionsof an ion across a large (or planar) interface, the maximumforward peak current IFWD

p may then be expressed by theRandles–Sevcik equation (Equation 16).(36)

IFWDp = 0.4463ziAFcw

i

√ziF

RT

√v

√Dw

i (16)

where A is the interfacial area, ν the rate of a potentialsweep, and cw

i the aqueous bulk concentration of i.

−60

−40

−20

0

I (μA

)

20

40

60

80

100

−0.1 0.0 0.1 0.2 0.3

Δowφo

TMA+ = 0.16 V

Δoφ (V)w

Figure 4 Cyclic voltammogram for the transfer of tetramethy-lammonium across the w/1,2-DCE interface at different sweeprates (the interfacial area is 1.13 cm2).



Together with the evaluation of the diffusion coefficientof the transferring ion, the determination of the formaltransfer potential of an ion (and thus of its Gibbs energyof transfer) is the most important application of CV. Fora reversible IT reaction at a large planar interface, �w

o φo′i

may be expressed in terms of the half-wave potential,�w

o φi,1/2, by Equation (17):

�wo φi,1/2 = �w

o φo′i + RT

2ziFln

(Dw

i

Doi

)(17)

Experimentally, �wo φi,1/2 is considered equal to the

mid-peak potential and is directly deduced from thevoltammograms. However, as the diffusion coefficientsin the organic phase are rarely known because ofexperimental difficulties, the ratio Do

i /Dwi in Equation

(17) is usually approximated to the inverse ratio of thesolvent viscosities, η, by application of Walden’s rule(36)

(Equation 18):Do

i

Dwi

= ηw

ηo(18)

Finally, for a reversible charge transfer, the classicalfollowing conditions also apply:

• the peak potentials must be independent of the scanrate;

• the peak-to-peak separation is 59/zi mV at 25 °C.

4.2 Hydrodynamic Methods

Common hydrodynamic methods can be applied to studyelectrochemistry at ITIES. One of the earliest examplesis the dropping electrolyte electrode, analogous to themercury-drop electrode. It permits very reproduciblemeasurements owing to the continuous renewal of theinterface for every drop and allows the study of bothIT and FIT reactions.(48 – 55) The principle consists ineither dropping down or dropping up an electrolytesolution and recording the current as in polarography.The methodology of polarography can then be transposeddirectly.

The introductions of gelled and supported liquid/liquidinterfaces have enabled the use of normal hydrodynamicmethods to study charge transfer at ITIES. Generally,the studies have focused on IT and FIT, using channelflow cells,(56) rotating membrane cells(57) and wall-jet techniques.(58) In the rotating membrane cell, theinterface is supported in a thin porous membranebetween inner and outer compartments of the cell,and the membrane rotation allows the formation ofhydrodynamic boundary layers similar to a rotating diskon both sides of the membrane.(57,59 – 61) Typically, onlythe membrane has been impregnated with the oil phase.

A similar approach has been to use rotating liquidmembrane disk attached on a glassy carbon electrodeto study IT,(62) or to use gelled rotating aqueous phaseplaced inside a small cylindrical cell.(63)

Wall-jet four-electrode cell with a membrane-stabilizedITIES has been used for amperometric detection ofCl−, ClO4

−, NO3−, SCN−, Br−, I−, and K+ by a flow-

injection analysis, with detection limits of about 0.5 μM.This approach was extended for crown ether-facilitatedalkali metal cation determination and to the detection ofAg+ in the presence of a suitable ligand and has beendiscussed in more detail in the review by Samec et al.(25)

Flow-injection cells (basically equivalent to the channelflow cell) have been used by several authors, asreviewed by Samec et al.(25) However, most of the studiesconcentrate on the analytical applications, but moredetailed investigations of channel flow cells have alsobeen published,(56,64) and digital simulations have beenperformed to model the responses of the cells.(65)

Flow cells have shown potential in many practicalapplications in the fields of electroanalysis(25) andliquid–liquid extraction of metals and drugs.(66 – 69)

The recent advances in electrochemically modulatedextraction have been reviewed by Arrigan et al.(70) andBocek et al.(71) (Section 5).

4.3 Micro- and Nanointerfaces Between TwoImmiscible Electrolyte Solutions

4.3.1 Micropipettes and Microholes

Microelectrodes benefit from diffusion fields controlledby the geometry of the interface and from reduced ohmiclosses. Because studies at ITIES always involve the useof an organic solvent, much effort has been dedicated tosupporting micro liquid/liquid interfaces, as described inreviews by Mirkin et al.(72) and more recently by Shaoet al.(73) Using the micropipettes technology developedfor electrophysiology, liquid/liquid interfaces were firstsupported at the tip of micropipettes (micrometer-sizedinterface between two electrolyte solutions, μITIES),the water phase being usually located inside the pipet.Micropipettes provide an asymmetry of diffusion fields.Ingress motion of ion occurs by pseudospherical diffusionto a microdisk interface, whereas egress motion out of thepipet occurs by linear diffusion. This yields asymmetricvoltammograms as shown in Figure 5.(74) The ingresscurrent reaches a steady-state value proportional to theradius, the diffusion coefficient, and a geometric factor,as given by Equation (19):(72)

ISS = KziFDwi cw

i r (19)

where K is a geometrical constant equal to 3.35 π for aglass pipette.



−0.2 −0.4 −0.8

Potential (V)

4.0

3.0

2.0

1.0Cur

rent

(nA

)

0.0

Figure 5 Video micrograph of a 15.5 μm radius micropipet filled with an aqueous KCl solution and immersed in a 1,2-DCEsolution of DB18C6. No external pressure was applied, and the micro ITIES is flat. The insets show the corresponding steady-statevoltammograms of facilitated transfer of potassium. (Reproduced with permission from Ref. 74. Copyright 1998, American ChemicalSociety.)

Dual micropipettes have been developed to studymore complicated reactions, as they can support twoindependent liquid/liquid interfaces that enable thegeneration/collection experiments. For example, thesepipettes have been used to study heterogeneous IT-coupled homogeneous chemical reactions of ionic speciesin solution and investigate the transfer of species limitingthe potential window.(72,73)

Another approach is to support μITIES in a microholein a thin polymer film or silicon structure.(73) A techniqueoften used to micromachine polymers is UV laserphotoablation,(75) whereas that used to machine siliconis anisotropic etching. For microinterfaces supported inmicroholes, the thinner is the supporting film, the moresymmetric are the diffusion fields. For very thin films,the mass transport equations are similar to those for amicrodisk electrode of radius r .(72,73) In this case, thehalf-wave potential is given by Equation (20)

�wo φi,1/2 = �w

o φo′i + RT

ziFln

(Dw

i

Doi

)(20)

and the steady-state current by Equation (21):

ISS = 4ziFDwi cw

i r (21)

This methodology can be used to determine the half-wave potentials of highly hydrophobic or hydrophilicions species that are otherwise not accessible by normalmethods.(76)

With thicker films, however, the microhole supportingthe ITIES modifies the mass transport, and both theingress and egress geometries in and out of the microholeinterface must be introduced.(72,73) Following the shapegiven in Figure 6, the expression of the half-wave potentialthen becomes

�wo φi,1/2 = �w

o φo′i + RT

ziFln

⎛⎜⎝Dw

i

Doi

hw + πr

4

ho + πr

4

⎞⎟⎠ (22)

The main advantage of working with micro liquid/liquidinterfaces stems from the low ohmic drop, which providesclean voltammetric responses.

The major barriers to the electroanalytical exploitationof amperometry at liquid/liquid interfaces have been themechanical stability of the interface and the resistivityof the organic phase. To circumvent these difficulties,the first approach has been to ‘gelify’ one of thephases (usually the organic phase) using the methodologydeveloped to produce polymer membranes for the designof ISEs (Figures 7 and 8a, b).



Organic phase

Solid materialsupporting the

interface

Aqueous phase

Spherical diffusion

Interface

Spherical diffusion

ho

hw

Line

ar d

iffus

ion

2r

Figure 6 Schematic diagram showing the diffusion processesof an ion passing from water to the organic phase through amicrohole-supported liquid/liquid interface. r is the radius ofthe microhole, hw the penetration depth of the aqueous phaseand ho that of the organic phase into the microhole.

Analyte

PET

Organic electrolyte gel layer

Organic reference aqueous layer (gel)

Combined reference/counter electrode

Figure 7 Simplified diagram showing the common composi-tion of an ionode. The interface is supported in a microholearray pierced through poly(ethylene terephthalate) (PET) bylaser photoablation.

Composite membranes comprising an organic elec-trolyte gel supported on a thin polymer micromachinedso as to include a regular array of microholes havebeen developed and named ionodes for simplicity.(77 – 79)

Another approach has been to use silicon-fabricatedmicro liquid/liquid interface arrays.(80)

4.3.2 Nanopipettes and Nanoholes

The development of the preparation techniques hasenabled to decrease the radius of the interface evenfurther, below 10 nm. The CVs observed on a nanopipettechange from an asymmetric to a pseudo-steady state as thesize of the interface decreases. Two theoretical models forthe egress IT have been developed, describing the pipetteshape with a hyberbola (Equation 23) or as a perfect cone(Equation 24).(73)

Iss ≈ πnFDcr sin θ (23)

105 μm

r = 11 μm

120

μm

(a)

(b)

Figure 8 Scanning electron micrographs of the entrance-sideholes in a PET film. (a) Empty holes and (b) array filledwith poly(vinyl chloride) (PVC) at 70 °C. (Reproduced withpermission from Ref. 77. Copyright 1997, Elsevier.)

Iss ≈ πnFDcrθ (24)

where θ is the tip angle. If θ is small, sin θ ≈ θ. Thevalidity of these equations was confirmed by digitalsimulations.(73) Nanopipettes have been useful for thedetermination of the kinetic parameters of fast charge-transfer reactions at ITIES, as this has been verydifficult at macroscopic ITIES because of uncompensatedresistance and charging currents. However, the validityof the obtained data is still a controversial subject, as thekinetic analysis can be complicated by the negative surfacecharge of the glass, resulting in current rectification, asdiscussed in the recent review by Samec.(15) The lowohmic drop of the nanopipettes also enables the use ofa wider range of solvents such as n-octanol, a standardsolvent for measuring the partition coefficient of drugsin pharmacy.(73) Another interesting approach is the useof a nanopipette-supported ITIES as an ‘electrochemicalattosyringe’: negative polarization of the oil phase in thepipette moves the meniscus of the interface sufficientlyfor some amount of aqueous solution to enter thepipette, and this process can be reversed by applyinga sufficiently positive potential on the pipette. Thevolume of aqueous solution entering the pipette (fromattoliter to picoliter) can be controlled by the variation



of the applied voltage.(73) Nanopipettes have also otherinteresting applications, for example, in scanning probetechniques and controlled deposition, as described inrecent reviews.(73,81)

Recently, nanoporous silicon nitride membranes havebeen used to form nano-ITIES arrays, showing improvedsensitivity compared to microarrays as shown by compar-ison of TEA+ transfer at micro- and nano-ITIES.(82 – 84)

4.4 Three-phase Electrodes

Another approach has been to use the three-phaseelectrode technique with a droplet of oil phase containinga redox mediator immobilized on an electrode.(85,86) Nowthe redox reaction at the electrode requires a transferof the ion into the immobilized phase to upkeep theelectroneutrality, and as only the soluble redox probeis required, studies of charge-transfer reactions acrossITIES can be extended to nonpolar solvents such as 2-octanol and n-octanol. This approach has been used tostudy the transfer of various anions and cations acrossw/NB, w/n-octanol, w/DCE, and w/NPOE interfaces, aswell as the facilitated transfer of alkali metals by crownethers. Complete listing is given in Ref. 13, and thistechnique has been described in more detail in recentreviews.(25,87 – 90) The alternative approach is to have adroplet of water on a metal electrode immersed in an oilphase.(91)

4.5 Spectroscopic Techniques

4.5.1 Optical Techniques

Spectroscopic techniques are interesting alternativesto classical electrochemical methods, because theyhave the advantage of providing in situ spectroscopicmeasurements at liquid/liquid interfaces. Two maintypes of optical experiments (namely voltfluorimetry orvoltabsorptometry on the one hand and sum-frequencygeneration (SFG) or second harmonic generation (SHG)on the other) are commonly conducted at ITIESdepending on whether linear or nonlinear optics,respectively, are used. For simplicity, however, only thelinear optical techniques are presented here, and readersinterested in SHG or SFG techniques should consultreviews.(92 – 98) A review by Fermin(99) covers also theother optical techniques in detail, so only a short overviewis given here.

Ultraviolet/visible (UV/VIS) absorption measure-ments can be carried out when the incident light beamimpinges on the interface from the phase of larger opticalindex in total internal reflection (TIR) geometry, i.e. withan incidence angle greater than the critical angle, so thatthe transmitted light wave in the adjacent phase cannotpropagate. Voltabsorptometry measures the changes of

light intensity of the reflected beam because of theabsorption of charge-transfer products. Assuming thatthe absorbance is proportional to the integral of the bulkconcentration of the absorbing species, its time derivativeis again proportional to the Faradaic current.(100) As anexample, Figure 9(a) and (b) show the evolution of theabsorbance in 1,2-DCE on transfer of methyl orange.(101)

The evolution of the UV/VIS spectra follows the currentchange in the corresponding voltammogram. The band at420 nm increases monotonically during the forward sweepowing to deprotonated methyl orange transfer from waterto 1,2-DCE and decreases only after the correspondingisobestic point after which the transfer is inverted.

This technique, as well as voltfluorometry, has beenused to study simple and facilitated IT as well as

0.4

0.3

0.2

0.1

0.0300 400 500 600

Abs

orba

nce

Wavelength (nm)

Q

H

A

(a)

G

40

30

20

10

0

−10

−20

−30

−40−280 −180

Δoφ (mV)w

20 120 320220

FWD

REV

AB

C

DE

F

HI

J

K

L

QPO

NM

(b)

I (μA

)

Figure 9 In situ UV/VIS spectra (a) and cyclic voltammogram(b) for the transfer of deprotonated methyl orange from waterto 1,2-DCE at a scan rate of 36 mV s−1. (Reproduced withpermission from Ref. 101. Copyright 1998, Elsevier.)



ET at ITIES, as described in the recent review.(99) Involtfluorometry, the change in fluorescence intensity froman exciting beam is monitored as a function of appliedinterfacial potential. Recently, these methods have beenapplied to three-phase electrodes using transparentindium-tin-oxide electrodes to study porphyrin-facilitatedtransfer of anions and coupling of the anion andET.(102,103)

The advantage of fluorescence and luminescencemeasurements is that the technique is extremely sensitiveand that small changes in interfacial concentration can bereadily monitored. In contrast to CV, these techniquesare totally specific to the transferring species and arenot influenced by the transfer of undesired species, suchas supporting electrolyte ions.(101) Furthermore, they areinsensitive to double-layer charging and ohmic drop, sothat chronoabsorptometry and chronofluorimetry(104,105)

studies proved to be very attractive in measuring thekinetics of IT(99,101) for which reliable data were previ-ously difficult to obtain. Other spectroscopic techniquesare also of interest in this field, such as time-resolvedlaser-induced fluorescence for monitoring the lifetimes ofexcited species(106) and potential-modulated reflectancespectroscopy,(99) where the transfer kinetics of a speciesare estimated by measuring its frequency-dependentabsorption following an ac potential perturbation. Poten-tial modulation spectroscopies are covered in a recentreview by Nagatani.(107)

Quasi-elastic light scattering (QELS) is a spectroscopictechnique to study the dynamics of the liquid–liquidinterface.(99,108) It monitors the frequencies of capil-lary waves generated by thermal fluctuations at theliquid–liquid interface and can be used to measure theinterfacial tension, surface excess of the electrolytes,and thus, differential capacitance of the interface. QELShas been used to study the adsorption of aqueous zincporphyrins and lipids on the liquid–liquid interface, aswell as assembly of gold nanoparticles at the interface.(99)

A more comprehensive review of the spectroscopictechniques to study liquid/liquid interfaces has beenrecently published,(109) not only limited to polarizedinterfaces.

4.5.2 Biphasic Electrospray Ionization MassSpectroscopy

Electrospray ionization mass spectrometry (ESI-MS) isa powerful tool for studying biological macromoleculesand their complexes. To apply this technique for highlyhydrophobic species, injection of inert oil phase (tolueneor heptane) into the aqueous flow prior to the ionizationwas used to study interfacial complexation of Cu2+and Fe2+ with a hydrophobic ligand.(110,111) To applythis system to study interfacial complexation reactions

at w/1,2-DCE interface, with the ligand in the oilphase, biphasic electrospray ionization mass spectrometry(BESI-MS) has been introduced. In this technique, thereactants were introduced to ESI tip with a dual channel,and the complexation took place only at the Taylor coneof the MS.(112) The same approach was used to investigatethat complexation of metal ions (charges from +1 to+3) with phospholipids,(113) and complex formation ofSr2+ with a phosphine oxide ligand at w/1,2-DCE andwater/RTIL interfaces.(114)

BESI-MS was also used, in combination with ITIESelectrochemistry, to show the complexation of peptideswith lipids. The stability of the complexes could alsobe studied by varying the temperature of the heatedcapillary of the MS,(115,116) and the effect of the Galvanipotential difference on the interfacial complex formationof proteins with lipophilic ions was also investigated.(117)

BESI-MS is a good analytical tool to addressthe potential-dependent interfacial complexation andcomplex formation at the interfaces, and it can offermechanistic information in combination with the electro-chemical techniques. This method could be extended tostudy homogeneous reactions initiated by charge transferat the ITIES.

4.6 Scanning Electrochemical Microscopy

Scanning electrochemical microscopy (SECM) is ascanning probe technique in which the current at theprobe is affected by the interface. It is a powerful toolto characterize the topography and local reactivity ofan interface. SECM has been applied to study the chargetransfer at liquid/liquid interfaces, giving valuable insightsabout ET kinetics and allowing the separate study of ETand IT.(118) The utilization of SECM at ITIES has beendiscussed in detail in several reviews.(119 – 121) SECM hasbeen used to study ET, IT and FIT, as shown in Figure 10.Submarine tips have been used to approach the ITIESfrom below, and typically, the interface has been polarizedby a common ion.

In a typical ET SECM/ITIES experiment, an ultrami-croelectrode (UME) probe is placed in a phase containingthe reduced redox species R1. The oxidized species O1 isgenerated on the tip and can be reduced in the interfacialET at ITIES. Hence, an increase in tip current (positivefeedback) is observed close to the ITIES. If no suitableredox mediator is present in the opposite phase, decreasein tip current (negative feedback) is observed close tothe ITIES, because of the hindered diffusion of R1. Thismethodology has been used to study ET between a seriesof redox species and also to investigate the effect of amolecular monolayer (for example, phospholipid layer)on the ET reaction.

Although most of the SECM studies have concentratedon ET, IT of redox active species can be studied by



(a)

(b)

(c) (d)ET

UME

Submarine UME

α

α

β

Micropipette

M+

M+

M+

X−

IT

μITIES

Hemisphericaldiffusion

Hindered diffusion

R1

R2O2

O1

Figure 10 The SECM studies of liquid/liquid interface between phase α and β, showing the hemispherical diffusion profile of thedisk UME in the bulk and the negative feedback because of hindered diffusion at the interface (a), submarine SECM configuration(b), positive feedback due to heterogeneous ET, with the electroneutrality balanced by the transfer of anion (c), and micropetteSECM probe for IT and FIT studies at ITIES (d). Either α or β phase can be used as oil phase.

depletion of the transferring species close to the interface,inducing the IT at ITIES. The same approach can be usedto study the transfer of neutral redox active species. Theuse of micropipet probes instead of electrodes allows theinvestigation of transfer of nonredox active ions, as shownin Figure 10. The same methodology can be transferredto study FIT.(119,120) In addition, SECM is a powerful toolto study homogeneous reactions induced by IT. Besidescharge-transfer processes at ITIES, SECM can be usedto study transfer of ions through pores of membranes oreven ion channels of bilayer lipid membranes.(73)

5 APPLICATIONS

5.1 Amperometric Ion Sensors and Detectors

Nonredox ionic species can be detected amperometricallyby measuring the current associated with IT reactionsacross a polarized ITIES.(25) However, the majordifficulties in designing transducers with liquid/liquidsystems stem from the mechanical instability of theITIES and the resistive nature of the organic phase.As can be deduced from Section 3.3, these two problemscan be circumvented by using microinterfaces such asmicropipets and microholes in thin polymer films orby gelifying one or two of the phases (although thediffusion coefficient of ions in a gel is much reduced).The literature of amperometric sensors utilizing ITIESuntil the year 2004 has been reviewed thoroughly bySamec et al.,(25) so only some of the most interesting orrecent developments are discussed here. This review isby no means comprehensive, as the subject would merita review of its own.

Plasticized polymers have been used to solidify theorganic phase and efficient amperometric sensors, forexample, for sodium, ammonium, choline and urea basedon FIT have been obtained, as described in Ref. 25.Direct IT or stripping IT reactions have been used inamperometric sensors with a water/NPOE–poly(vinylchloride) (PVC) gel interface supported on an arrayof microholes, and selective amperometric sensors havebeen achieved with suitable ionophores.(25) For example,detection of lithium in samples of blood serum containinga large excess of sodium,(122) and a detection systemof single sodium salts based on ionodes with a highsensitivity (1 ppt) in amperometric pulse potential modehave been demonstrated.(123) These results are verypromising because they constitute a powerful alternativeto conductimetric detection of nonredox species inion-exchange chromatography,(124) which suffers froma lack of selectivity compared with optical or directamperometric detectors (Figure 11a and b).(79)

These sensors have successfully been used as detectorsfor capillary zone electrophoresis, with performancecomparable with the state of the art detectors employedusually.(125,126) Recently, an amperometric thin-layerelectrochemical flow cell sensor based on membrane-supported ITIES was demonstrated for nanomolardetection of TEA+. This technique increased thesensitivity of the amperometric sensors based on ITIESby the factor of 10–1000.(127)

Another interesting approach has been to use protonselective sensors to analyze the products of enzymaticdecomposition of the analytes. A single microhole,fabricated by simple mechanical puncturing was usedas a μITIES, and the facilitated proton transfer byETH1778 was used to analyze the glucose content of the



700600500

A BC

62

60

58

56

54

52

50

48300 400

t (s)

t (s)

I (nA

)

(a)

(i) (iv)

(v)

(vi)

(vii)(ix)

(viii)

(ii)

(iii)

300150 450 600 750 900 1050 1200

Con

duct

ivity

(μS

cm

−1)

(b)

10μS cm−1

A B C

(i) (iv)

(v)(vi) (ix)

(viii)

(vii)

(ii)

(iii)

Figure 11 (a) Pulse amperograms recorded for monovalentcations facilitated by 1 mM valinomycin using a PVC–NPOEmicrogel membrane and tetrabutylammonium cation as organicsupporting electrolyte. (b) Chromatogram obtained for themonovalent cations based on a conductimetric detector. Theconcentrations of the standard solutions are (A) (i) 100 ppmNa+, (ii) 0.5 ppm NH+

4 , and (iii) 0.5 ppm K+; (B) (iv)100 ppmNa+, (v) 1 ppm NH+

4 , and (vi) 1 ppm K+; and (C) (vii)20 ppm Na+, (viii) 4 ppm NH+

4 , and (ix) 4 ppm K+. Flowrate, 0.85 mL min−1; 5 mM tartaric acid is used as the eluent.(Reproduced with permission from Ref. 79. Copyright 1998,ACS.)

sample. Similar approach was used to detect paraoxon,an organophosphate neurotoxin, and parathion andmethyl parathion: protons were produced by enzymatichydrolysis of the analyte and detected amperometricallywith the microhole sensor.(128 – 130)

A recent development has been to use silicon-fabricated μITIES arrays, for example, in detectionof oligopeptides, dopamine, and propranolol.(80,131 – 133)

Also, ionic liquids have been used as oil phase for thesearrays,(134) and a flow-injection sensor based on theseμITIES arrays has been demonstrated.(135)

Most of the published applications are for determi-nation of cations, but the progress with developingmethods to analyze anions has not been as successful,because of the lack of suitable complexing ligands foranions. However, as understanding of anion complexation

increases, suitable ionophores are developed, showinggreat promise for anion-selective sensor development.(136)

Coulometric detectors can be utilized as well, both forelectroanalysis and ion extraction. The electrolysis cellsused for this purpose have been recently reviewed byKihara et al.(137) One of the most promising constructionshas a porous Teflon tube with a metal wire immerged inthe oil phase. Aqueous flow (flowing around the metalwire) is applied with a syringe pump into the tube, sothat high surface area ITIES is achieved, as shown inFigure 12.(138)

Precise coulometric determination of various anionsand cations has been demonstrated, as well as the selectiveseparation of UO2

2+ from Sr2+ and La3+.(137)

5.2 Macromolecule Sensing at Liquid/Liquid Interface

5.2.1 Macromolecule Sensing

ITIES has been also successfully used for macromoleculesensing, with the analytes ranging from low-molecular-mass substances (e.g. neurotransmitters, amino acids,drugs) through to proteins and nucleic acids, as describedby recent reviews by Arrigan et al.(139,140) There has alsobeen a growing interest in label-free protein detection atITIES. The overall process of protein interaction at ITIESis quite complicated and usually involves adsorption ofthe proteins at the interface and a complex formationwith the counter anion of the oil phase. These processeshave been investigated for insulin,(141) hemoglobin,(142,143)

lysozyme,(117,144) and polylysine dendrimers,(145) also atarrays of μITIES.(146,147) Behavior of globular proteins,including cytochrome c, ribonuclease A, lysozyme,albumin, myoglobin, and α-lactalbumin in the presenceof different anionic surfactants was studied at ITIES,showing that, in principle, online electrochemical sepa-ration and determination of proteins could be done with

Organicsolution (O)

Porousteflontube 100 μm

0.8 mm

1 mm

2 m

m

O

O

W

Winterface

Ag/AgCl wire

Pt wireAqueoussolution (W)

Reference-electrode (O)

(a) (b)

Figure 12 Flow electrolysis cell with porous PFTE resin tubefor precise coulometry (a). Sectional view of the PTFE tubeequipped with a metal wire (b). (Reproduced with permissionfrom Ref. 138. Copyright 2009, John Wiley & Sons Ltd.)



a two-step oil/water flow-cell system.(148) The observedvoltammetric signal was shown to be influenced by thesurface properties of a protein, indicating that electro-chemistry at ITIES can be utilized to characterize theseproperties.

Electrochemistry at ITIES has also been used to inves-tigate chemical denaturation,(149) enzymatic proteolysisof proteins,(150) and protein unfolding.(151) Complexationof DNA with acridine-functionalized calixarene has alsobeen investigated at ITIES. Calixarene-facilitated IT wasdiminished by the complexation with DNA, providingthe basis for DNA hybridization detection at ITIES.(152)

Interactions of chitosan with picrate and eosin wererecently characterized at ITIES,(153) and extraction ofheparin molecules (molecular weights up to 20 kDa)facilitated by a carefully designed ionophore has beendemonstrated, aiming into a development of ampero-metric heparin sensor.(154)

These recent developments demonstrate that electro-chemistry at ITIES has many potential applications forelectroanalytical macromolecule sensing, and they offera new approach for characterization of macromolecules.Hence, this area is expected to receive a growing interestin the future.

5.2.2 Chiral Detection

Investigations have shown that the energies of transferfor chiral ions into chiral solvent differ: a chiral solventfavors the transfer of an anion of the same chirality bya couple of kilojoules per mole. Although this differenceis small, this approach could have some use in chiraldetection.(155 – 157) Another approach has been to utilizeenantioselective FIT, using cyclodextrins as complexingagents in the oil phase.(158) ITIES can also be used to studychiral interactions of drugs. The complexation of oneenantiomer of protonated propranolol by a glycoproteinin a physiological buffer decreased the observed currentfor IT across ITIES, as the complexed species does nottransfer, allowing the determination of the associationconstants for both enantiomers.(159)

5.3 Analytical Aspects of Metal Extraction

The chemical analysis of liquid solutions has for along time been a very important domain of analyt-ical chemistry.(160) Numerous applications in biology,medicine, and environmental studies require the sensi-tive and selective detection of chemical constituents indifferent media. Heavy metals are an example where theneed for a precise analytical tool is of major importanceowing to their high toxicity toward life in general andpeople in particular.

Electrochemistry at the ITIES has attracted muchattention in this field during the past decade, because itprovides a simple way of measuring the stoichiometry andthe association constants of ion–ionophore complexesin organic solvents.(161 – 163) With the rapid develop-ment of coordination chemistry, numerous ligandswith specific binding properties have become available,extending complexation reactions where the transfer ofa monocharged metal ion is facilitated by the formationof a complex of 1:1 ion-to-ligand stoichiometry to morecomplicated systems.

Theoretical studies on FIT reactions now provide areliable framework to analyze experimental data anddetermine the physicochemical parameters governingcomplexation reactions at ITIES. Matsuda et al.(164)

published a general theoretical equation for the polaro-graphic response of reversible FIT reactions, leading to aprediction of the half-wave potential dependence on theinitial concentrations of both the metal and the ionophore(denoted cM,init and cL,init). In ligand excess, the transferis limited by the diffusion of the free metal ions towardthe interface, whereas it is limited by the diffusion of thecomplex away from the interface in metal excess. Betweenthese two limiting cases, a mixed diffusion regime isestablished and, for 1:1 stoichiometry, the authors deter-mined criteria separating these three regions in whichthe dependence of �w

o φ1/2 on the initial concentrationschanges (Figure 13a and b). They further described asimple method to calculate the association constants,and this work has been widely used to interpret bothpolarographic and cyclic voltammetric experiments.

Few studies have been carried out to model cyclicvoltammetric experiments(165 – 168) and the approachfollowed by Matsuda et al. has recently been generalizedto 1 : m ion-to-ligand stoichiometries, showing that varia-tions of cM,init and cL,init do not lead to a similar evolutionof �w

o φ1/2.(169,170) This is illustrated in Figure 12(a) and(b) and demonstrated by the relationships obtained forthe TIC, TID, and TOC mechanisms (Equations 25–27).

When cL,init >> cM,init,

�wo φ1/2 = �w

o φMz+,1/2 − RT

zFln

⎡⎣ m∑

j=0

βoj (cL,init )

j

⎤⎦ (25)

when cM,init � cL,init,

�wo φ1/2 = �w

o φo′Mz+ − RT

zFln

⎡⎣ m∑

j=0

jβoj cMinit

(cLinit

2

)j−1

⎤⎦

(26)



1:41:3

1:2

1:1IIIII

I

1:2

1:3 1

1

zF/R

T

Log (cLinit)

Metal excess Ligand excess

(a)

1:1

1:4

1:1 to 1:4

IIIII I

1:1

1:2

1:31:4

zF/R

T

Log (c Minit)

Ligand excess Metal excess

(b)

Δ oφ1

/2w

Δ oφ1

/2w

Figure 13 Schematic diagram showing the half-wave potentialdependence on (a) the initial ligand concentration and (b) theinitial metal concentration for TIC/TID facilitated ion-transferreactions of 1:1 to 1:4 ion-to-ligand stoichiometry. Anintersection point has been chosen arbitrarily to facilitatecomparison between the various stoichiometries. These schemesshow that these curves do not have equal slopes in metal orligand excess and that a transition domain separates these twoextreme cases (the roman numbers indicate the domains definedby Matsuda et al.,(164) who derived criteria defining these threeregions).

where βoj is the reduced association constant, defined as

βoj =

coMLz+

j

coMz+(co

L)j=

j∏k=1

Koak (27)

The theory of FIT has later been improved to includealso competitive complexation between different ionsand also ligands as well as to describe the effects ofprotonation of the neutral ligands.(12,171)

A comprehensive list of species and systems studiedfor simple and facilitated IT (ranging from simple alkalimetal cations to transition metals and even actinyls andincluding ionized drugs and other organic compounds)has been given in the recent reviews by Dassie et al.,(12,13)

with more than 550 references. As the amount ofliterature published is so huge, readers interested indetailed listings should consult these reviews.

Most of the facilitated transfer reactions follow a TICor TID mechanism,(37) and only a few studies showevidence of an ACT mechanism,(172,173) because mostligands used in electrochemistry are poorly soluble inwater, so that complexes may only be formed in theorganic phase. Furthermore, the TOC mechanism has notbeen differentiated from the TIC mechanism, because thisnecessitates kinetic data that still remain unmeasurable,the diffusion being the factor limiting the transfer andnot the energy required to allow the ions to cross theinterface.

5.4 Electrochemistry of Drugs at Liquid/LiquidInterfaces

Because of their intrinsic nature, interfaces betweentwo immiscible liquids may serve as simple artificialmodels of biological membranes. Therefore, studies ondrug-transfer characteristics and mechanisms in suchsystems are of great importance to understand better thebehavior of drugs in their pharmacokinetic phase,(174,175)

their distribution in vivo,(176) and hence, the deliveryproblems that limit their efficiency.(177) The transportof exogeneous chemicals (and hence of the majority ofcommon drugs) is a passive process,(178) for which it iscommonly assumed that ionizable compounds can onlycross biological membranes in their neutral form.(179)

However, later studies suggest a significant passivetransfer of ions.(180 – 183) As many drugs are organiccompounds that are thus partly or largely ionized atphysiological pH, membrane transport can be deeplyaffected by the lipophilicity of charged species.(184) Thelipophilicity of a species is generally evaluated by itspartition coefficient, defined as the logarithm of theratio of the activity of a species in the organic phaseto that in the aqueous phase and denoted log P . Thisparameter is widely used in medicinal chemistry to relatethe structure and the physicochemical properties of adrug to its biological activity,(185) which is the objective ofall quantitative structure–activity relationship (QSAR)studies.(186)

Dealing only with ions for which log P is directlygiven by the formal transfer potential,(187) electrochem-istry at the ITIES appears to be a method of choicefor assessing the lipophilicity of ionizable drugs. Theliterature is still very scarce on this topic, and IT voltam-metry has only been applied to determine the transfer



700

600

500

400

300

200

100

0

−100

−2000 1 2 3 4 5 6 7 8 9 10 11 12 13 14

TH22+ (w)

TH22+ (w) TH+ (w)

TH+ (w)

TH+ (w)H+ (w)

H+ (w)

H+ (w)

H+ (w)

H+ (w)

T (o) TH+ (o)

T(o)T(w)

=11

TH+ (o)

TH+(o)

TH22+ (o)

TH22+ (o)

TH22+ (w)

TH+(o)

T(w)

pH

Δ oφ

(mV

)w

Figure 14 Ionic partition diagram of trimetazidine at 25 °C in water–1,2-DCE. The figure shows the formal transfer potentialsobtained by cyclic voltammetry as a function of aqueous pH (bold circles), the equiconcentration lines between two adjacent species(bold dashed lines) and the corresponding transfer mechanisms (chemical equilibria). T, TH+ and TH2+

2 stand for the neutral, thesingly protonated and the doubly protonated forms of trimetazidine, respectively. (Adapted from Reymond et al.(223) by permissionof Plenum Publishing Corporation)

potentials of a few compounds of biological interest (1,10-phenanthroline,(188,189) acetylcholine,(58,190 – 192) variousamines,(55,193,194) phosphorylation uncouplers,(195,196)

pyrazolone derivatives,(197) picrate,(47,198 – 200) cinchoni-dine,(54) and quinine(187,201 – 203)) and investigate thetransfer of several antibiotics(204 – 207) and a seriesof hypnotic, anesthetic, cholinergic, and adrenergicagents,(208 – 212) as well as the transfer of some β-blockers.(213,214)

The transfer of ionized drugs across a liquid membranehas also been studied for a series of catamphiphilicdrugs(215) and local anesthetics,(216) and the transfer ofa group of drugs with different pharmacological activities(verapamil, clomipramine, tacrine, and imipramine)was studied at liquid membranes with two polarizedinterfaces.(217)

Another approach to determine log P has been touse the three-phase electrode technique with a dropletof oil phase containing a redox mediator immobilizedon an electrode (Section 4.3).(86) Gulaboski et al. usedthis methodology to determine the partition coefficient ofanionic drugs in NB and NPOE, and compared the valuesobtained with the three-phase system utilizing n-octanol,gaining also useful information about solvation propertiesof anionic drugs in nonaqueous solutions.(218,219)

The introduction of ionic partition diagrams(202) (whichare a transposition at liquid/liquid interfaces of Pourbaix’spH–potential diagrams(220) for metals in solution) hasimproved the understanding of the partition processesof ionizable compounds, since they allow reliable predic-tions and interpretations of their transfer mechanismsacross ITIES, as exemplified by Figure 14 for the caseof trimetazidine. Further insight into the influence of

electronic structure on lipophilicity has revealed theimportance of intramolecular charge delocalization tostabilize ions in the organic phase.(221 – 224) Althoughthis effect has not yet been quantified, electrochem-istry at ITIES is an easy methodology to assess thepH–lipophilicity profiles of ionizable drugs.

The use of the ionic partition diagrams was extendedto zwitterionic drugs such as cetiritzine, azapropazone,tenoxicam, raclopride, and eticlopride.(225,226) The effectof ligands such as cyclodextrin or cholesterol on the IT hasalso been investigated to help to characterize effects ofligands (such as pharmaceutical excipients) on partitionbehavior. These ligand shift partition diagrams help tounderstand noncovalent interactions of functional groupsof the drug molecules.(227,228) The use of a commercial96-well microfilter plate was shown to present a rapid andefficient way to determine partition diagrams of ionizeddrugs,(229) and the methodology was further improved bythe use of a commercial pH gradient gel.(230)

Electrochemical extraction of cationic drugs fromartificial urine has also been demonstrated, indicatingthat partition diagrams could also be useful for selectiveextraction of drugs.(68)

It must finally be noted that electrochemistry at n-octanol/water interface is not possible with the traditionalmethodology,(213) so that most electrochemical studiesuse 1,2-DCE or NB as the organic phase. In orderto interpret the lipophilicity of ionizable drugs inpharmacological terms, the thermodynamic parametersobtained with these solvents must be correlated to theoctanol–water system commonly used in pharmacology.This correspondence has been established,(231) offeringmore relevance to the results presented above and



opening ideal perspectives for extending electrochemicalmeasurements to medicinal chemistry.

Log Pliposomes has been shown to correlate betterwith the pharmacokinetic parameters in humans thanlog Poct.

(232) Electrochemistry at the μITIES with 1,2-DCE phase supported in a micropipette has been usedto determine the partition coefficient of five differentβ-blockers between aqueous phase and liposomes (logPliposomes) in a fast and simple method.(233)

Liquid–liquid interface offers also a possibility tostudy the membrane activity of drugs. ITIES can bemodified with a monolayer of lipids with Langmuirthrough,(234 – 237) and this set-up can be used to gainvaluable information about how different functionalgroups of the drug molecules affect the interactions withthe lipid monolayer.(238,239)

6 CONCLUSION

The increasing number of experiments conductedat liquid/liquid interfaces shows that electrochemicalmethodologies at such boundaries can be an efficientand versatile tool to probe ions. The great demand forinnovative analytical techniques with accurate sensitivityand high selectivity offers a brilliant future for ITIES.Electrochemistry at ITIES is truly a versatile field, withthe applications ranging from solvent extraction, sepa-ration, transfer-phase catalysis, and photochemistry tobiomembrane studies. In recent years, there has been agrowing interest to use ITIES to study molecular elec-trocatalysis for oxygen and CO2 reduction and hydrogenevolution,(240) and even a fuel cell utilizing a liquid/liquidinterface has been demonstrated.(241)

Furthermore, the study of charge-transfer processesgives an insight into the fundamental problems of physicalchemistry in biphasic systems. Thanks to the improvedtheoretical understanding of interfacial structure, thetransfer process of solvated ions from one phase to theother becomes clearer, but it is still very demandingbecause future applications of ITIES will depend on ourtheoretical knowledge of the motion of ions in biphasicsystems.

ACKNOWLEDGMENT

The authors thank the Academy of Finland (Grant No.133261) for financial support.

ABBREVIATIONS AND ACRONYMS

ACT Aqueous Complexation followed byTransfer

BATB Bis(triphenylphosporanylidene)Ammonium Tetrakis(pentafluorophenyl)Borate

BATPBCl Bis(triphenylphosphoranylidene)Ammonium Tetrakis(4-chlorophenylBorate)

BESI-MS Biphasic Electrospray Ionization MassSpectrometry

CV Cyclic VoltammetryDB18C6 Dibenzo-18-crown-6 DBS

1,3:2,4-Dibenzylidene SorbitolDNA Deoxyribonucleic AcidESI-MS Electrospray Ionization Mass

SpectrometryET Electron TransferFIT Facilitated Ion TransferISE Ion-selective ElectrodeIT Ion TransferITIES Interface Between Two Electrolyte

SolutionsμITIES Micrometer-Sized Interface Between

Two Electrolyte SolutionsNaTPB Sodium TetrabutylborateNB NitrobenzeneNPOE o-Nitrophenyl Octyl EtherMS Mass SpectrometerO Oxidized SpeciesPET Poly(ethylene terephthalate)PVC Poly(vinyl chloride)QUELS Quasi-Elastic Light ScatteringQSAR Quantitative Structure–Activity

RelationshipR Reduced SpeciesRTIL Room Temperature Ionic LiquidSECM Scanning Electrochemical MicroscopySFG Sum-frequency GenerationSHG Second Harmonic GenerationTBACl Tetrabutylammonium ChlorideTBATPB Tetrabutylammonium TetraphenylborateTEACl Tetraethylammonium ChlorideTIC Transfer by Interfacial ComplexationTID Transfer by Interfacial DecomplexationTIR Total Internal ReflectionTOC Transfer followed by Organic-phase

ComplexationUME UltramicroelectrodeUV/VIS Ultraviolet/Visiblew Water1,2-DCE 1,2-Dichloroethane



LIST OF SYMBOLS

a ActivityA Interfacial Areac Concentration

D Diffusion CoefficientF Faraday Constanth Penetration Depth of a Phase into a MicroholeI Current

IFWDp Maximum Forward Peak Current

Ka Association ConstantP Partition Coefficientr Radius of the InterfaceR Gas Constantt Time

T Temperaturex Positionz Charge

Greek Letters

βj Reduced Association Constant of the MLjComplex

�wo φ Galvani Potential Difference Between the

w and o Phases�w

o φoi Standard Transfer Potential of i

�wo φo′

i Formal Transfer Potential of i�w

o φoi,1/2 Half-wave Potential

�Go,w→ot Standard Transfer Gibbs Energy of a

Species i from Phase w to Phase oφ Inner Potentialη Solvent Viscosity

μo Standard Chemical Potential or GibbsEnergy of Solvation

ν Rate of a Potential Sweepθ Nanopipette tip angle

θ = cwi

coi

= exp[

zF

RT(�w

o φ − �wo φo

i )

]

ξ =(

Dwi

Doi

)1/2

Superscripts

o Organic Phasew Aqueous Phaseo Standard Valueo′ Formal Value

FWD Forward* Bulk Value

Subscripts

i Ion iliposomes Between Liposomes and Water

L Ligand or Ionophoreinit Initial

M Metal IonML Metal–Ionophore Complexoct Between n-Octanol and Water+ Positive Ion− Negative Ion

SS Steady Statet Transfer

RELATED ARTICLES

Biomedical Spectroscropy (Volume 1)Biomolecules Analysis: Introduction

Environment: Water and Waste (Volume 3)Detection and Quantification of EnvironmentalPollutants • Flow-injection Techniques in EnvironmentalAnalysis

Pharmaceuticals and Drugs (Volume 8)Pharmaceuticals and Drugs: Introduction • QuantitativeStructure–Activity Relationships and ComputationalMethods in Drug Discovery

Electroanalytical Methods (Volume 11)Electroanalytical Methods: Introduction • Chemilumine-scence, Electrogenerated • Ion-selective Electrodes:Fundamentals • Pulse Voltammetry

Electroanalytical MethodsElectrochemical Detection Methods Following LiquidChromatography, Capillary Electrophoresis, andMicrochip Electrophoresis Separations

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