Advances in the Voltammetric Analysis of Small Biologically Relevant Compounds

Analytical Biochemistry 303, 1–16 (2002) doi:10.1006/abio.2002.5584, available online at http://www.idealibrary.com on

REVIEW Advances in the Voltammetric Analysis of Small Biologically Relevant Compounds Nathan S. Lawrence,* Emma L. Beckett,* James Davis,† and Richard G. Compton* ,1 *Physical and Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, Oxford, OX1 3QZ, United Kingdom; and †Department of Chemistry, University of Surrey, Guildford, Surrey, GU2 7XH, United Kingdom

Received November 2, 2001; published online February 25, 2002

The problems associated with attempting to apply voltammetric techniques to the analysis of biologically relevant organics within complex media are identified and, through reviewing the very recent literature (1999 –mid-2001), possible solutions are described. The boundaries of the search were limited to research targeted at the resolution of specific problems, associated with quantitative determinations. Various strategies have emerged to counter problems of poor sensitivity and selectivity and these have been summarized and critically appraised. Where possible, the characteristics of each approach have been distilled into a table format to ease comparison. Emphasis has been placed on the collation of information that will improve the intrinsic electrode response and as such should be of value to those interested in pursing electroanalytical methodologies regardless of context. © 2002 Elsevier Science (USA)

Key Words: electroanalysis; voltammetry; electrochemical detection; review.

Electrochemical techniques are versatile tools to probe biochemical pathways and mechanisms (1). Their implementation for routine analysis however has hitherto found limited advocates despite the low cost inherent in electrochemical instrumentation, particularly when compared with spectroscopic and chromatographic systems (2, 3). Perceptions of poor sensitivity, selectivity, and reproducibility obtainable in the analysis of real-world samples are deep-rooted and in the 1

To whom correspondence and reprint requests should be addressed. Fax: 01865 275410. E-mail: richard.compton@chemistry. ox.ac.uk. 0003-2697/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved.

past have often been justifiable. A number of developments have recently led to a resurgence in the use of electroanalytical protocols. Manipulation of electrode surfaces with catalytic species and selective barriers and the evolution of hybrid techniques focus on retaining quantitative integrity of the measurement: This paper highlights the progress made. We first summarize the problems in electrochemical methods that have required solving. The analysis of authentic samples necessarily puts the electrode at the mercy of the matrix constituents. A number of key problems can arise as a consequence. As with most analytical methodologies, acquiring sufficient selectivity is of prime importance. Electroanalytically accessible species comprise a potentially enormous group that tend to possess a narrow range of chemical functionalities that are amenable to redox interconversion. The most common groups that are exploited as quantifiable redox labels are phenolics, aromatic amines, thiols, heterocyclics, quinoids, and the nitro and nitroso groups. A host of voltammetrically visible inorganic anions also appear within biological media (typically nitrogen and sulfur oxo anions). In aqueous solution and barring the effect of adsorption, electrodes are usually blind to alkyl, hydroxy, and amine groups; carboxyl, carbonyl, and nitrile functionalities; and organo halides. There are of course a number of exceptions, particularly in the case of carbohydrates and amino acids; these are discussed below. Problems can arise however when two or more species possessing similar redox properties coexist within the sample. Increased voltammetric resolution through the application of pulse techniques such as differential pulse and square-wave voltammetry may allow the discrimination between the target and the interferent. 1

2

LAWRENCE ET AL.

Overlapping signals may however lead to ambiguities in baselines. In a multicomponent mixture, discrete separation of the signals may not be possible if one component is in massive excess to that of the others such that a single, unresolved voltammetric peak may be observed. Thus, a working knowledge of the limitations of the technique and the likely sample composition is clearly advantageous. Poor electrode sensitivity can arise as a consequence of slow electrode kinetics (exemplified by the response to cysteine at glassy carbon) or through contamination of the electrode surface. Passivation of the working surface is a common example and can occur through the buildup of surface oxides or the adsorption of organic debris (or indeed the target analyte itself). While most contaminants will be endogenous to the sample, an additional source of contamination can actually arise as a consequence of performing the electrochemical measurement. This is typified by attempts to determine phenolic species (i.e., tyrosine) through the electrooxidation of the hydroxyl functionality. Polymeric material can be deposited on the electrode surface (4, 5) and although profitably exploited as a method of electrode modification (6, 7), the cumulative decrease in electrode response tends to preclude this route as a means of quantifying the original, monomeric, species. Similar behavior is also observed with aromatic amines and heterocyclics such as pyrroles, thiophenes, and indoles (6 – 8). Conversely many analytical protocols actively exploit the adsorption process. Accumulation of the target analyte at the electrode surface through adsorption can provide considerable gains in sensitivity. Reproducibility however is an issue that needs to be addressed. Irrespective of the substrate employed, reproducible control over the composition of the electrode– solution interface before, during, and after the measurement process is a major prerequisite to the development of a viable analytical protocol. The literature review was conducted with the aim of collating information relating to strategies that have been targeted at alleviating obstacles to poor electrode performance rather than those dealing simply with the quantification of a particular target in a given medium. The boundaries of the search were restricted to voltammetric techniques with the emphasis placed on protocols aimed at utilizing chemical and physical methods to improve intrinsic electrode response toward the analysis of organic compounds, predominately of physiological or pharmaceutical significance. Coverage of metal ion analysis and bioelectrocatalysis has largely been eschewed in this instance given the availability of numerous reviews on these subjects (9 –13); however, it is likely that most strategies described herein will be of considerable significance to these areas and, as such, should complement existing reference sources. The

data presented therefore provides a representative snapshot of current electroanalytical methodologies. The various approaches have been categorized and are discussed in turn in the following sections. In general, the data were obtained through examining electroanalytical papers published within the past 3 years and where appropriate the characteristic aspects of each paper have been distilled into tabular format. Protocols in which the electrochemical technique is the predominant methodology (4, 14 –111) are detailed in Table 1 while those that have been assimilated within either liquid chromatographic (112–148) or capillary electrophoretic (149 –173) configurations are summarized in Tables 2 and 3, respectively. The reader is directed to the Appendix for a more detailed brief on the structure adopted in the construction of the tables and the abbreviations used therein. ANALYSIS MEDIUM

The medium in which the analysis is conducted will be an important arbiter of what can be analytically exploited. While organic solvents can significantly expand the potential ranges open to electrochemical investigation, difficulties attributed to the management of such systems (electrolyte solubility, volatility, disposal, etc.) and the predominance of aqueous samples have tended to restrict such media to fundamental studies. Nevertheless, a number of protocols have used organic solvents for purely electroanalytical purposes and a few have sought to exploit the favorable partitioning of the analyte into the nonaqueous layer. In doing so, improvements in both sensitivity and selectivity are possible through the preconcentration of the analyte within the organic layer while interferences are retained within the aqueous layer. The extraction of phenolics into chloroform (89) and vanillin into ethylacetate (109, 110) represent two of the more successful attempts. ELECTRODE SUBSTRATE

It can be seen from the tables that most applications utilize traditional electrode materials such as carbon, platinum, and gold with improvements in response conferred through supplementary modifications to the electrode surface. Judicious choice of the base material itself however can be used to enhance the electrode performance but more importantly ensures that a quantifiable signal can be obtained. Thus, the large hydrogen overpotentials exhibited by mercury-, carbon-, and boron-doped diamond opens up an extensive cathodic window within which reduction processes can be exploited (typically those involving nitroso (75, 76) and nitro (77) groups). This contrasts the use of conventional metallic electrodes as the onset of hydrogen

3

VOLTAMMETRIC ANALYSIS OF BIOLOGICAL COMPOUNDS TABLE 1

Direct Electrochemical Detection Target analyte

Substrate

3,4-Dichlorophenoxyacetic acid Adenosine Adriamycin Albendazole Alcohols Allergens/serotonin Amines Amino Acids

SPE C-F GC Hg GC Au C Hg, GC, G, Cu

Amitrole Amoxicillin Anthracycline/nogalamycin Antioxidants Ascorbate

Pb CPE Hg

BHT Arbutin Carbohydrates Carbovir Catechol Ceftazidime Dimenhydrinate Diquat Doxazosin Ethanol/acetaldehyde Flufenamic Acid Fluoroxamine Glutathione Glycerol Hydrazine Indanthrene/indigo Isoxsuprine/fenoterol Kojic acid Mitoxantrone Neurotransmitters

GC, Pt SPE Cu, Pt Pt G, C-F Hg/C/CPE Hg GC CPE Au Hg SPE CPE Ni-Cr Pt Au, GC, CPE, Pd, Pt Hg SPE Co-C-F BDD, CRAM, GC, C, Pt, C-A, CPE, G

Nimesulide Nitrite Nitropyrene NO

Hg Au, GC GC C-F, GC, Pt, Ir

Paraquat Peroxynitrite Pesticide/phenol/PAH Phenolics Prazosin Protamine Purines Retinol, retinal, retinoic acid Rifamycin Roxarsone Rutin/Flavonoids S-Triazines Sulfur compounds Surfactants Tetrahydrocarbazol Tetramethylthiuram disulfide Theophyline Thiamine Triclosan Tricyclic antidepressants Vanillin Zn pyrithione

GC Pt/C-F Au/C C-F, GC CPE Au BDD, C-F GC-Hg, GC-Pb Hg CPE CPE Cu/GC Hg Hg CPE Pt PbRuO Hg SPE CPE G, C-F CPE

Pt, CPE, SPE, GC, Au-A

Comments Molecular imprinting Electrochem. treated Ni implanted GC AdSV–copper(II) complex Anionic clay Array detection/nafion Derivatization via quinone adducts AdSV Ni(II) complex; mechanically immobilized CuFe(CN) 6 ; derivatization—catechol; chemometric; sinusoidal voltammetry Nafion, RuO Poly(vinylimidazole) AdSV Polypyrrole/Fe(CN) 6n- , Ru-diphenyldithiocarbamate; cyclodextrin/ferrocene; RuO; MnO 2 ; 2,6-dichlorophenolindophenol; Tosflex/Fe(CN) 6n- ; electrodeposited Pd Chemometric; polypyrrole/NiPc Clay Metal binding/pulsed/FIA, Fehlings reagent; dual pulse Microelectrode; SWV Poly(N-vinylamide); laser activation/electrochemical pretreatment Poly(lysine) Cu complexation Nafion/Mn catalytic system C-8 modified, Nafion Nafion Acridone derivative AdSV CoPc NiOOH SAM PAD, alternating current voltammetry Derivatization–nitrosation Electrochem. treated Modified carbon fiber Electrochem. treated; Nafion or laponite; montmorillonite/in vivo; Os(bypy)/Nafion; Electrochem. treated/Nafion; derivatization— borate ester; poly(Malachite green); Poly(eugenol); chemometric; CoPc/FIA; Os(PVP)/Nafion AdSV 3-Mercaptopropanoic acid; derivatization—phloroglucinol Electrochem. treated NiPc/Nafion/poly(1,2-diaminobenzene)/poly(resorcinol); electrodeposited NiPc; poly(neutral red)/Nafion; NiPc/Nafion; MPc (M ⫽ Co, Ni, Cu)/Nafion; NiCr 2 O 4 modified electrode Mn/Nafion MnPc/PVP Microarrays Chemometric; laser ablation; solvent extraction AdSV/Nafion SAM/Fe(CN) 6 /Ru(NH 3 ) 6 Electrochem. treated; fast scan voltammetry Hg and Pb thin films AdSV Amberlite AdSV/FIA FIA Indirect via H 2 S Indirect via H 2 O 2 Pt modified CPE Interdigitated microelectrode array on Si wafer Nafion AdSV Cyclodextrin Solvent extraction MxOy M ⫽ Sn, Cr, Pb, Cd, Cu, Zr, Bi

Ref. 14 15 16 17 18 19 20 4, 21–25 26 27 28 29–35

36, 37 38 39–42 43 44, 45 46, 47 48 49 50, 51 52 53 54 55 56 57 58, 59 60 61 62 63–74

74 75, 76 77 78–84

85 86 87 5, 88, 89 90 91 92–95 96 97 98 99 100 101 102 103 104 105 106 107 108 109, 110 111

4

LAWRENCE ET AL. TABLE 2

Liquid Chromatographic–Electrochemical Detection Target analyte

Substrate

Comments

Ref.

3-Nitrotyrosine Acetaminophen Alditols Aliphatic amines Amino acids Amino sugars Antioxidants Antioxidants—BHT Carbohydrates Dinitropyrene Haloacetic acid Iodate Neurotransmitters Oxalic acid Peptides Peroxides Polyacrylate dust Resveratol Sulfur antibiotics Thiols Tobramycin

Au-Hg GC Au GC GC, C-SG, Au-Ni, CRD

Reduction of nitro then oxidation of amino-OH CuPc PAD Derivatization—phenylisothiocyanate InFe(CN) 6/Nafion; NiOOH; bromide/bromine PAD amperometric electrode set NiPc/polypyrrole NiPc Poly(1-naphthylamine)/Cu(II); PAD Nitro group reduction Nafion MoO layer Redox cycling; poly(2-methylthiophene) CoPc Derivatization Dual parallel electrodes; CuPtCl 6 Indirect via ethanol recovery/PAD Multichannel array PAD

112 113 114 115, 116 117–121 122 123 124 125–130 131 132 133 134–138 139 140 141, 142 143 144 145, 146 147 148

GC GC GC, Au GC C GC BDD, GC, C-F, CRD CPE C-F GC Pt GC BDD, Au BiPbO 2 Au

PAD

ion reduction, particularly in acidic media, may obscure the analytical signal. While the cathodic latitude offered by carbon is somewhat less than that of mercury, in many instances it is sufficiently negative for it to allow carbon substrates to serve as a viable and less toxic alternative to the liquid metal. The use of mercury has been frowned upon in recent years and is in notable decline as concerns over toxicological effects and issues relating to the handling and disposal of the material have mounted (174 –177). Nevertheless, the ability to re-

peatedly generate a fresh, atomically smooth and reproducible electrode surface through a controlled hanging-drop action greatly simplifies the collection and interpretation of consecutive measurements especially in highly fouling media. In contrast, regeneration of solid electrodes can often require mechanical polishing to remove organic deposits prior to each new measurement. Abrasion of the surface inevitably introduces a degree of irreproducibility through variations in active surface area. The procedure can be further complicated by the need to apply electrochemical conditioning of the

TABLE 3

Capillary Electrophoresis–Electrochemical Detection Target Amino acids—cysteine Carbohydrates Clozapine Erythomycin Ferrocene Glutathione Hydrazine Illegal drugs Neurotransmitters Phenols Pipemidic acid Polycarboxylic acids Purine alkaloids Reserpin Thiols

Substrate Pt, Au-Hg, Au, SPE C, Cu C-F-A Hg-TF

Comments

Ref.

Bromide/bromine; Derivatization—o-phthaldialdehyde/mercaptoethanol CuO

149–151 152, 153 154 155 156 157 158 159 160–164 165–167 168 169 170 171 172, 173

Microband-redox cycling Au-Hg SPE Pt C-F-A, C-SG, Au, SPE C-F, Au-SPE, Pt C-F-A Cu C C-F-A GC

Pd electroplated Redox cycling; micromachined; Screen-printed gold electrode

MPc, powder electrode

VOLTAMMETRIC ANALYSIS OF BIOLOGICAL COMPOUNDS

renewed surface to remove capacitive effects that would otherwise obscure the analytical signal. Despite the advantages possessed by mercury, a narrow anodic range and design limitations tend to limit its applicability. Safety considerations necessarily override all selection criteria and as such the electroanalytical community is committed to the use of solid electrodes and the pursuit of alternative substrates. Some interim compromises have been reached however with mercury film (96, 155) and amalgam electrodes (112, 151, 157) filling niche applications, such as in the analysis of sulfur moieties where mercury–thiolate interactions can be exploited (151, 157). The use of copper electrodes to determine carbohydrates (39, 41, 42, 153) and amino acids (25, 178 –184) is an apt example where appropriate choice of substrate can be critical. Neither carbohydrates nor amino acids (with the exception of tyrosine, tryptophan, cysteine) are particularly amenable to electrochemical interrogation at conventional electrode materials but display marked reactivity at copper surfaces. Oxidation of the copper electrode in alkaline media results in the formation of a layer of insoluble copper oxide (178, 179). The presence of analytes capable of complexing copper ion serve to increase the solubility of this layer. This induces further dissolution of the copper substrate with the corresponding increase in the oxidative current related to the amount of analyte present (179). An alternative route involves the electrocatalytic oxidation of the analyte at the electrode surface with CuO(OH) believed to function as a redox mediator (180 –184). A similar mechanism has also been proposed for the use of nickel electrodes (56, 185). Optimization of electrode substrates through the fabrication of composite materials has also been pursued and take a number of forms. Metal alloys (Cu/Ni (186), Pt/Ir (82), Ni/Ti (185) and Ni/Cr (56)) have been found to enable performance enhancements beyond those attainable with either constituent metal. Their use has tended to lie within specific areas. A similar fate has befallen amalgam electrodes with few being exploited outside of the area of thiol analysis (151, 157). The most successful implementations of composite technology have been the carbon paste and sol gel electrode assemblies. This can be attributed largely to the ease with which the electrodes can be prepared and the diversity of material that can be incorporated within the electrode bulk. Some of the variations are detailed in the accompanying tables for comparative purposes; however, a number of excellent reviews have been compiled on the chemical and electroanalytical versatility of these materials and therefore the reader is directed to these for more comprehensive information (187, 189).

5

Screen-printed electrodes (SPEs) 2 can in many respects be viewed as a composite electrode as the processing ink is often loaded with a variety of ingredients that can include components whose function is to improve the intrinsic electrode response (31–33, 38). The great strength of SPE technology lies in the ability to create large numbers of near identical electrodes that can be used in a single shot context. This can offer the possibility of avoiding many of the pitfalls associated with cumulative electrode passivation and contamination. As the technology for creating such electrodes has matured, the emphasis has shifted slightly from disposability to the ease with which complex electrode architectures such as interdigitated arrays can be patterned (162). While the resolution of the individual electrode structures may be confined to micrometer level, it can represent an extremely effective, low cost, and more accessible alternative to photolithographic techniques. ELECTRODE PREPARATION

Electrochemical pretreatment of the working surface has been shown to provide a facile means by which both the sensitivity and the selectivity can be improved. Pulsed amperometric detection has evolved largely to combat the passivation effects that are associated with oxide formation on metallic electrodes (almost invariably gold (114, 122, 126 –130, 145, 148)). This approach is typically employed within postcolumn detection systems where disassembly of the detection unit is to be avoided. Thus, electrode pretreatment is usually conducted directly in the carrier electrolyte prior to each measurement cycle through the imposition of a complex, multipotential waveform. A typical example involves poising the electrode at a positive potential, to oxidatively clean the surface followed by a reductive potential to remove the surface oxide and reactivate the metal surface. The final stage in the waveform typically involves adjusting the electrode to a potential at which the target can be detected. Numerous variations exist and are usually tailored to the application in question. Preconditioning has also been used with carbon electrodes and particularly in the case of carbon fibers where it has been shown to provide a more stable baseline (93). This is a prerequisite for those systems employing fast scan voltammetry where subtraction of the baseline from the signal is necessary in order to aid interpretation of the data (93). Aggressive oxidation of carbon electrodes however leads to a proliferation of carboxyl functionalities on the surface (15, 45, 61, 67, 77, 92–95). When the electrode is immersed in a solu2 Abbreviations used: SPE, screen-printed electrodes; RAM, random arrays of microelectrodes.

6

LAWRENCE ET AL.

FIG. 1. Schematic representation of redox cycling at an individually addressable electrode array.

tion possessing a bulk pH that is greater than the pK a of the surface moieties, deprotonation occurs resulting in a functionalized surface bearing anionic groups. Electrostatic repulsion of anions (typically ascorbate) is complemented by the preconcentration of cationic species (dopamine) and often results in a significant improvement in the voltammetric discrimination between the two (67). Somewhat surprisingly, borondoped diamond can also succumb to electrochemical conditioning with the creation of carboxyl functionalities shifting the ascorbate signal to more anodic potentials and thereby providing greater resolution between the interferent and dopamine (63, 92). A similar procedure has been invoked to resolve mixtures of ascorbate and urate (92–94). ELECTRODE ARRAYS AND REDOX CYCLING

Most electroanalytical applications use a conventional three-electrode configuration with a single working electrode. Arrays of microelectrodes have been making increasing inroads into the field of electroanalysis and bring with them a number of distinct advantages over traditional cell configurations. Array assemblies can provide an enhanced current while retaining the advantages that are inherent to single microelectrodes (190, 191). Most tend to be employed as detectors within flow systems in capillary electrophoresis (154, 163, 168, 171) applications. Assuming that the potential at each electrode within the array can be individually controlled, enhanced currents can be achieved through a process of redox cycling. A simple example is shown in Fig. 1. Analyte is oxidized at one electrode (denoted as the generator) and is subsequently reduced at the neighboring electrode (the collector). The small distance between electrodes within the array (typically nanometer to micrometer) allows diffusion of the analyte between the electrodes to induce a redox cycle that amplifies the current. Redox cycling can also be used to negate the influence of electroactive interferences. This approach relies on exploiting the difference in electrochemical reversibility between analyte and interferent. An interferent that exhibits irreversible electrochemical

behavior will be capable of undergoing reaction at one electrode (the generator) but will fail to be regenerated at the neighboring collection element in the array. Thus, if the analytical signal is derived from the current recorded at the collector, the contribution from the interferent would be expected to be negligible. This effect has been successfully demonstrated with dopamine/ascorbate mixtures whereby repeated recycling of dopamine at the array could enable the detection of the latter in the presence of a substantial excess of ascorbate (134, 161, 163). More sophisticated configurations are possible and their analytical implementation has been reviewed previously (190 –192). Array technologies have traditionally been localized within centers possessing microfabrication facilities and thus usually constructed to meet the demands of a specific application. A novel alternative and arguably more accessible form of array technology has recently become available in which hundreds (or thousands) of carbon fibers are extruded and encapsulated within an epoxy resin. At one end, the carbon fibers are connected to a single electrical contact (essentially each fiber becomes wired in parallel) while at the other end the epoxy is polished to expose the working surface. This comprises a random assembly of micrometer diameter fibers and providing that there is no overlap of the diffusion zones, the electrode retains the characteristic response expected of a microelectrode albeit at a tremendous amplification and a capacitance increased in proportion to the number of electrodes (64, 193). While still in their relative infancy, the applicability of random arrays of microelectrodes (RAMs) has been demonstrated through the determination of dopamine with low nanomolar limits comparing favorably with most of the approaches detailed within Table 1. MODIFIED SURFACES

Significant enhancements in sensitivity can, in some instances, be brought about through the use of electrocatalysts. These can be divided into two divisions: enzymatic and nonenzymatic catalysis. The breadth of the former precludes its inclusion within the current report and has been extensively summarized (10 –13). Nonenzymatic electrocatalysts, while lacking much of the specificity inherent to biological systems, are often more robust and amenable to electrochemical manipulation. This is highlighted by the fact that commercial glucose sensors couple inorganic redox mediators (usually a ferrocene or hexacyanoferrate moiety) to the biological recognition element (glucose oxidase) in order to extract a viable analytical signal. Electron transfer mediators are used predominately to enhance the sensitivity of the electrode response to analytes that tend to exhibit slow electrode kinetics at the bare, unmodified electrode substrate. Such cases

VOLTAMMETRIC ANALYSIS OF BIOLOGICAL COMPOUNDS

FIG. 2. Schematic representation of electrocatalysis at a polymer modified electrode.

are typified in the analysis of thiols (4, 22, 55, 120, 121, 147) and nitric oxide (78 – 83) where osmium complexes (66, 73), mixed valence hexacyanoferrrate metallates (Fe (29), Cu/Fe (22), In/Fe (120)) and metallophthallocyanines (M ⫽ Co (55, 72, 83, 139), Cu (83, 113), Ni (37, 78, 79, 82, 83, 123, 124), Mn (86), Fe (81)) are routinely used to improve the electrode performance. The basic mechanism through which these systems operate is detailed in Fig. 2. While early implementations simply involved the addition of the catalyst to the assay solution, most contemporary protocols confine the mediating species to the electrode surface. Retention of the catalyst is clearly advantageous from an economic standpoint but more importantly it improves the flexibility of the system through providing an option for reagentless sensing. Impregnating the bulk electrode material with the catalyst is one of the simpler options and is commonly encountered with composite electrodes such as those based upon screen-printed carbon (31–33), carbon paste (30, 55, 72, 111, 139, 188), and sol gels (189). In the last two examples, this has the advantage that renewal of the electrode surface through mechanical polishing can be achieved without incurring any loss of the catalytic species and represents one of the more facile methods of electrode modification. The distribution of the catalytic species throughout the electrode material is particularly advantageous in situations where the electrode surface has become irrevocably contaminated. Renewal of the surface through polishing while exposing fresh catalysts therefore bypasses the need for subsequent electrode modification. Localization of the mediator within a polymeric film is an alternative option and can be achieved through coordination to ligands present within the polymer backbone (92) or through simple electrostatic entrapment (29, 37, 49, 66, 81– 83, 85, 123). In the case of macrocyclic species, electrooxidation of groups that constitute the ligand (usually pyrrolic functionalities within phthallocyanines) can result in the formation of an insoluble catalytic layer upon the electrode surface (79, 86). Electrodeposition of the catalyst is not restricted to organic species with the repetitive potential

7

cycling of mixed valence hexacyanoferrate metallates leading to the growth of inorganic films that have proven to be versatile mediators in the determination of thiols (120). This approach tends to provide a controllable method through which the catalyst can be immobilized and has particular relevance when considering the modification of microelectrode electrode assemblies. It must be acknowledged however that leaching of the mediator can occur, particularly in the case of inorganic moieties placed within flow systems, and as such they are often employed in conjunction with a conventional membrane such as Nafion (120). The addition of a polymeric film can also fulfill a number of complementary roles. Interferences can be minimized and the target analyte preconcentrated as a consequence of the chemical and physical composition of the polymeric barrier. In addition, molecular sieving by the film can prevent contamination of the underlying electrode substrate by macromolecular species. Nafion has been extensively exploited in electroanalytical applications with the anionic nature of the film proving particularly valuable when applied to physiological matrices. This has traditionally been typified by the exclusion of ascorbate in the determination of catecholamines (64, 66, 67), though its use in the discrimination of nitric oxide from endogenous nitrite has risen to considerable prominence (78 – 84) as interest in the physiological determination of NO has increased. Cationic polymers such as polyvinylpyridine (73, 86) and polypyrrole (29, 37) have also been used but chiefly as a means of encapsulating an anionic redox catalyst. DERIVATIZATION/INDIRECT DETECTION

Derivatization and indirect methods are usually employed to counter problems of selectivity or electrochemical accessibility. Chemical manipulation of samples to improve signal resolution is common among the core analytical methodologies and indeed central to chromatography, but the exploitation of such practices within the electrochemical community has received comparatively little attention. While the manipulation of peripheral functional groups, for example, may influence the column retention of an analyte, the electron withdrawing power of the new functionality may be insufficient to significantly alter the electronic properties of a core redox label. This is particularly true when dealing with spatially distant redox labels where inductive and field effects attributed to the modification may be less significant. The most common recourse has been to introduce an entirely new redox label onto the target analyte with the aim of placing the analytical signal within a potential region where there are few natural interferences (4, 20, 53, 60, 68, 76). In addition, the electrochemical conversion of the appended redox group may confer other advantages such as improved

8

LAWRENCE ET AL.

FIG. 3. Indirect determination employing the electrochemical interconversion of bromide/bromine at a dual electrode assembly.

sensitivity. Both aspects are typified by the use of nitrite-induced nitrosation of 1,3,5-trihydroxybenzene as a means of detecting the former (76). Rather than deriving the analytical signal from the one electron oxidation of the anion, the four-electron reduction of the nitroso group provides an inherently more sensitive path that occurs at a potential where ascorbate inference is negligible. This approach can be turned on its head with the addition of excess nitrite used to introduce a nitroso group onto an aromatic system that can subsequently be used as a tag through which a nonelectroactive analyte can be quantified (60). Derivatization can also be of benefit where the target is generally unreactive within the available potential window. This is exemplified by the determination of alkyl amines after coupling with quinone moieties (20). An alternative approach is to introduce a chemical oxidant or reductant and detect the resulting products. The most common example is the use of bromine in postcolumn detection strategies (118, 119, 150). Bromine is relatively indiscriminate and will react with a range of compounds including amines, thiols, thioethers, disulfides, and unsaturated compounds (150, 194). The acquisition of selectivity can therefore only be achieved through separating the constituents of the matrix prior to reaction with the bromine. In principle, bromine can be introduced directly into the postcolumn channel; however, a more facile route is to introduce bromide into the precolumn carrier stream (118, 119, 150). A dual electrode configuration is used first to electrogenerate the bromine and then to monitor its consumption through reaction with the matrix components. The basic mode of operation is highlighted in Fig. 3. Bromide coelutes with each component and is electrochemically oxidized to bromine at the first electrode in the dual electrode assembly. Unreacted bromine is then reduced at the downstream electrode with any depression in the baseline current proportional to the concentration of analyte (150). A brief inspection of the tables reveal a variety of indirect strategies and it must be acknowledged that a

great many have been reported within the scientific literature prior to the compilation of this review. In many instances, the birth of an electrochemical assay results from a specific need to monitor a particular analyte and the enlightened exploitation of some aspect of its chemistry. While in some instances, the approach may have a degree of generic applicability, as shown by the examples above, most are specific to either a given application or type of analyte. Thus, the electro-initiated reaction of catechol with thiol species (4) is selective for a range of sulfydryl thiols while protocols relying on the complexation of the target with a metal ion inevitably tend to be specific to the particular pairing (17, 21, 39). HYBRID SYSTEMS

The fusion of electrochemical detectors with liquid chromatographic and capillary electrophoretic systems represents the more successful and identifiable incursions of electrochemistry into conventional analytical methodologies. Electrochemical detection has since proven to represent a highly effective means of detection and has demonstrated sensitivity that in numerous cases has proven to be superior to that of UV detection and often comparable to fluorescence (53, 195–199). The implementation of electrodes as postcolumn detectors have been extensively reviewed for both LC and CE applications (197–199) and as such are not covered here in any depth. An examination of the detection limits that are available to the various techniques, regardless of methodology, reveals a spread of sensitivities. It is clear that irrespective of resolution, the end result will be subject to the performance of the electrode assembly employed. Postcolumn detection is equally susceptible to the vagaries of surface effects and is evidenced by the proportion of research papers employing some form of counter measure (varied substrates, dual electrodes, modified electrodes, post- and precolumn derivatization, pulsed detection/cleaning). The approaches taken to improve the electrode performance are not dissimilar to the direct electroanalytical protocols detailed in Table 1 and a symbiotic effect clearly exists. A more recent addition to the growing collection of hybrid technologies has been sonoelectrochemistry. The fusion of ultrasound technology with conventional electroanalytical protocols has been found to be particularly beneficial to the quantification of metal ions within matrices that have proven intractable for traditional electrochemical protocols (200, 201). The imposition of a high-intensity ultrasonic field within the cell results in a massive increase in mass transport that greatly improves sensitivity. The principal advantage possessed by this approach over other convective sources tends to lie in the generation and subsequent

VOLTAMMETRIC ANALYSIS OF BIOLOGICAL COMPOUNDS

9

CONCLUSIONS

FIG. 4. Schematic representation of cavitational bubble collapse and the corresponding in situ cleaning action associated with sonoelectroanalysis.

collapse of cavitation bubbles at the surface of the electrode. These processes provide an ablative action that efficiently removes adsorbed material from the electrode surface and maintains electrode activity, Fig. 4. Most reports to date have focused on metal analysis but the applicability of the technique for aiding the analysis of organic compounds (ascorbate (202), dopamine (203), and 5-aminosalicylic acid (204)) has been demonstrated. An alternative approach to retaining electrode activation has been laser ablation voltammetry in which adsorbed organic debris is thermally desorbed from the electrode. This has been used for the removal of polymeric depositions encountered in the analysis of phenolics (5) and the ascorbate oxidation productions (202). The general applicability of the approach for routine analysis is open given the capital cost involved in combining a high-power laser with the electrochemical system. Nevertheless, it has proven to be a versatile method through which the electrode activation can be maintained without disruption to the cell assembly and therefore may have value in a situation where highly reliable continuous online/at line monitoring is required. The fusion of electrochemical techniques with atomic and mass spectroscopic instrumentation has similarly been dominated by the field of metal analysis (205). In such instances the plating out of metal ions onto the surface of the electrode provides a method through which the target analyte can be preconcentrated. The accumulated metal is then oxidatively stripped from the surface and drawn into the inlet of the spectrometer. The extrapolation of such procedures to organic compounds clearly presents the possibility of improving selectivity with the potential-dependent physisorption of organic species at the electrode essentially extracting the target from interferences. Medium exchange followed by a relaxation in the applied potential could therefore release the accumulated organic compound in much the same way as that observed with metal ions (206).

It may be unrealistic to expect electrochemical techniques to directly compete with established analytical methodologies, and much ground has been lost to spectroscopic and chromatographic systems, as is evident in the relative absence of automated electrochemical systems. It is also clear from the contents of this review that the acquisition of selectivity and sufficient sensitivity still plagues the electroanalytical chemist. The account contained within has brought to light a common evolutionary pattern for commercially successful techniques: a novel strategy is designed for a specific requirement and is continually modified and simplified until it has generic applicability. It would however be unrealistic to expect to see commercial success for all the advances discussed in the review to come to fruition. Many of the composite substrates, such as metal alloys, and mercury film and amalgam electrodes seem destined for niche applications, amalgam electrodes rarely being used outside the study of sulfur moieties. Systems using arrays of microelectrodes have until recently had difficulty in achieving widespread appeal, the complexity of their construction being such that they are unable to progress away from in-house manufacture. The simplifications inherent in RAMs have however brought forward a similar technology with greater accessibility. Electrode substrate modifications abound within the literature, yet here again, the complexities associated with the fabrication of such assemblies often serves to preclude their widespread adoption. Within specific areas of study modified electrodes are however producing excellent results with polymeric barriers providing significant enhancements in selectivity though analytical robustness continues to be an enduring problem, in particular screen-printed electrodes, carbon paste electrodes, and sol gels where the catalyst is contained within the electrode material. Two areas of high interest for electroanalytical chemists lie in in vivo monitoring and hybrid technologies. The suitability of electroanalytical techniques to miniaturization and its proven success upon specific modification with authentic matrices display great potential for the technology’s use in the niche application of in vivo studies. Numerous hybrid technologies on the other hand show great potential for widespread acceptance and use of electroanalytical technologies. Sonoelectrochemistry and laser ablation voltammetry offer considerable promise. Liquid chromatography and capillary electrophoretic systems with electrochemical detection have however been receiving a lot of interest, with electrochemical detection as an alternative to UV or fluorescence proven highly satisfactory. It is clear however, that the methods discussed and continuing advances

10

LAWRENCE ET AL.

within the field have the potential to abolish remaining preconceptions concerning the inapplicability of electrochemical techniques to genuine matrices. APPENDIX

The tables have been prepared such that the target analytes have been listed in alphabetical order within the broad classifications of direct, LC-ED and CE-ED techniques. Where a report has investigated the response of more than two analytes these have tended to be grouped under an inclusive label. Thus, separate entries can be found for dopamine and neurotransmitters though the former can be classed within the latter heading. Similar examples prevail for thiols and amino acids. A discrete entry for a particular analyte is only given where the report has focused directly on its response or determination. In instances where the entry comprises a group, the limit of detection quoted will refer to the most sensitive result quoted. A list of abbreviations (excluding the common elemental assignations) that have been used throughout each table is provided below.

AdSV Au-A Au-Hg BDD C-F C-F-A CPE C-RAM C-R-D C-SG ED GC G Hg-TF PAD Pc SAM SPE

Adsorptive stripping voltammetry Gold electrode array Gold amalgam electrode Boron doped diamond Carbon fiber Carbon fiber array Carbon paste electrode Random array of carbon microelectrodes Carbon ring disk Carbon/Sol gel composite electrode Electrochemical detection Glassy carbon Graphite Mercury thin-film electrode Pulsed amperometric detection Phthallocyanine Self-assembled monolayer Screen-printed electrode

REFERENCES 1. Dryhurst, G. (1985) in Comprehensive Treatise of Electrochemistry (Srinivasan, S., Chizmadzhev, Y. A., Bockris, J. O’M., Conway, B. E., and Yeager, E., Eds.), Vol. 10, pp 131–188, Plenum, New York. 2. Bauer, H. H., and O’Reilly, J. E. (1986) in Instrumental Analysis (Christian, G. D., and O’Reilly, J. E., Eds), pp. 1–13, Allyn & Bacon, Needham Heights, MA. 3. Stulik, K. (1999) Challenges and promises of electrochemical detection and sensing. Electroanalysis 11, 1001–1004. 4. Lawrence, N. S., Davis, J., and Compton, R. G. (2001) Electrochemical detection of thiols in biological media. Talanta 53, 1089 –1094.

5. Fulian, Q., and Compton, R. G. (2000) Laser activated voltammetry: Application to the determination of phenol in aqueous solution at a glassy carbon electrode. Analyst 125, 531–534. 6. Sadik, O. A. (1999) Bioaffinity sensors based on conducting polymers. Electroanalysis 11, 839 – 844. 7. Cosnier, S. (1999) Biomolecule immobilization on electrode surfaces by entrapment or attachment to electrochemically polymerized films: A review. Biosens. Bioelectron. 14, 443– 456. 8. Emr, S. A., and Yacynych, A. M. (1995) Use of polymer-films in amperometric biosensors. Electroanalysis 7, 913–923. 9. Brainina, K. Z., Malakhova, N. A., and Stojko, N. Y. (2000) Stripping voltammetry in environmental and food analysis. Fres. J. Anal. Chem. 368, 307–325. 10. Davis, J., Vaughan, D. H., and Cardosi, M. F. (1995) Elements of biosensor construction. Enzyme Microb. Tech. 17, 1030 –1035. 11. Nikolelis, D. P., Hianik, T., and Krull, V. J. (1999) Biosensors based on thin lipid films and liposomes. Electroanalysis 11, 7–15. 12. Berggren, C., Bjarnason, B., and Johansson, G. (2001) Capacitive biosensors. Electroanalysis 13, 173–180. 13. Cass, A. E. G. (Ed.) (1990) Biosensors—A Practical Approach, p. 35– 43 and references therein, Oxford Univ. Press, New York. 14. Schollhorn, B., Maurice, C., Flohic, G., and Limoges, B. (2000) Competitive assay of 2,4-dichlorophenoxyacetic acid using a polymer imprinted with an electrochemically active tracer closely related to the analyte. Analyst 125, 665– 667. 15. Abou El-Nour, K., and Brajter-Toth, A. (2000) Sensitivity of electrochemically nanostructured carbon fiber ultramicroelectrodes in the determination of adenosine. Electroanalysis 12, 805– 810. 16. Hu, J. B., and Li, Q. L. (1999) Voltammetric behavior of adriamycin and its determination at Niion-implanted electrode. Anal. Sci. 15, 1215–1218. 17. Abu Zuhri, A. Z., Hussein, A. I., Musmar, M., and Yaish, S. (1999) Adsorptive stripping voltammetric determination of albendazole at a hanging mercury drop electrode. Anal. Lett. 32, 2965–2975. 18. Ballarin, B., Seeber, R., Tonelli, D., and Zanardi, C. (2000) Anionic clay modified electrode for detection of alcohols: An electrocatalytic amperometric sensor. Electroanalysis 12, 434 – 441. 19. Okochi, M., Yokouchi, H., Nakamura, N., and Matsunaga, T. (1999) Electrochemical detection of allergen in small-volume whole blood using an array microelectrode: A simple method for detection of allergic reaction. Biotechnol. Bioeng. 65, 480 – 484. 20. Rose, M. J., Lunte, S. M., Carlson, R. G., and Stobaugh, J. F. (1999) Hydroquinone based derivatization reagents for the quantitation of amines using electrochemical detection. Anal. Chem. 71, 2221–2230. 21. Wang, L. Z., Ma, C. S., Zhang, X. L., and An, Z. S., (1999) Determination of trace arginine by adsorptive voltammetry of its nickel(II) complex. J. Ind. Chem. Soc. 76, 116 –117. 22. Shankaran, D. R., and Narayanan, S. S. (1998) Studies on copper hexacyanoferrate modified electrode and its application for the determination of cysteine. Bull. Electrochem. 14, 267– 270. 23. Saurina, J., Hernandez-Cassou, S., Fabregas, E., and Alegret, S. (2000) Cyclic voltammetric simultaneous determination of oxidizable amino acids using multivariate calibration methods. Anal. Chim. Acta 405, 153–160. 24. Brazill, S. A., Singhal, P., and Kuhr, W. G. (2000) Detection of native amino acids and peptides utilizing sinusoidal voltammetry. Anal. Chem. 72, 5542–5348.

VOLTAMMETRIC ANALYSIS OF BIOLOGICAL COMPOUNDS 25. Zen, J. M., Kumar, A. S., and Chang, M. R. (2000) Electrocatalytic oxidation and trace detection of amitrole using a Nafion/ lead-ruthenium oxide pyrochlore chemically modified electrode. Electrochim. Acta 45, 1691–1699. 26. Uslu, B., and Biryol, I. (1999) Voltammetric determination of amoxicillin using a poly (N-vinylimidazole) modified carbon paste electrode. J. Pharm. Biomed. Anal. 20, 591–598. 27. Ibrahim, M. S. (2000) Voltammetric behaviour and determination of the anthracycline antitumor drug nogalamycin. Anal. Chim. Acta 409, 105–112. 28. Alonso, J. G., Sanchez, C. D., Garcia, M. L. T., Barbado, M., and Batanero, P. (1999) Electrocatalytical properties of a potassium hexacyanoferrate (II) modified polypyrrole electrode: Application to vitamin C determination. Anal. Lett. 32, 1961–1980. 29. Nalini, B., and Narayanan, S. S. (2000) Amperometric determination of ascorbic acid based on electrocatalytic oxidation using a ruthenium(III) diphenyldithiocarbamate-modified carbon paste electrode. Anal. Chim. Acta 405, 93–97. 30. Wu, J., Suls, J., and Sansen, W. (2000) Amperometric determination of ascorbic acid on screen-printing ruthenium dioxide electrode. Electrochem. Commun. 2, 90 –93. 31. Turkusic, E., Milicevic, V., Tahmiscija, H., Vehabovic, M., Basic, S., and Amidzi, V. (2000) Amperometric sensor for L-ascorbic acid determination based on MnO 2 bulk modified screen printed electrode. Fres. J. Anal. Chem. 368, 466 – 470. 32. Florou, A. B., Prodromidis, M. I., Tzouwara-Karayanni, S. M., and Karayannis, M. I. (2000) Fabrication and voltammetric study of lanthanum 2,6-dichlorophenolindophenol chemically modified screen printed electrodes: Application for the determination of ascorbic acid. Anal. Chim. Acta 423, 107–114. 33. Zhang, G. R., Wang, X. L., Shi, X. W., and Sun, T. L. (2000) beta-Cyclodextrin-ferrocene inclusion complex modified carbon paste electrode for amperometric determination of ascorbic acid. Talanta 51, 1019 –1025. 34. Zen, J. M., Tsai, D. M., Kumar, A. S., and Dharuman, V. (2000) Amperometric determination of ascorbic acid at a ferricyanidedoped Tosflex-modified electrode. Electrochem. Commun. 2, 782–785. 35. Liu, G. D., Li, Z. Q., Huan, S. S., Shen, G. L., and Yu, R. Q. (2000) Electro-catalytic oxidation of ascorbic acid at a cobaltsalen polymer modified electrode and analytical applications. Anal. Lett. 33, 175–192. 36. Ni, Y. N., Wang, L., and Kokot, S. (2000) Voltammetric determination of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate and tert- butylhydroquinone by use of chemometric approaches. Anal. Chim. Acta 412, 185–193. 37. de la Fuente, C., Acuna, J. A., Vazquez, M. D., Tascon, M. L., and Batanero, P. S. (1999) Voltammetric determination of the phenolic antioxidants 3-tert-butyl-4-hydroxyanisole and tertbutylhydroquinone at a polypyrrole electrode modified with a nickel phthalocyanine complex. Talanta 49, 441– 452. 38. Shih, Y., and Zen, J. M. (2000) An electrochemical sensor based on a clay-coated screen-printed electrode for the determination of arbutin. Anal. Chim. Acta 412, 63– 68. 39. Weber, G., and Messerschmidt, J. (2000) Total determination of metal-binding carbohydrates in plant extracts by using FIA with electrochemical detection. Fres. J. Anal. Chem. 367, 356 – 358. 40. Bessant, C., and Saini, S. (1999) Simultaneous determination of ethanol, fructose, and glucose at an unmodified platinum electrode using artificial neural networks. Anal. Chem. 71, 2806 – 2813.

11

41. Fitsev, I. M., Bakanina, Y. N., Abdullin, I. F., and Budnikov, G. K. (1998) Voltammetric flow-injection determination of glucose in blood serum. Ind. Lab. 64, 426 – 427. 42. Bakanina, Y. N., Abdullin, I. F., Budnikov, G. K., Fitsev, I. M., and Khabibullin, M. D. (1999) Voltammetric determination of sugar in wines and wine materials using a copper electrode. Ind. Lab. 65, 350 –351. 43. Lemoult, S. C., Cheng, Y., Kontturi, K., and Schiffrin, D. J. (2000) Electrochemistry of anti-HIV agents. Electrochem. Commun. 2, 244 –247. 44. Strein, T. G., Ximba, B. J., and Hamad, A. H. (1999) Steadystate voltammetry of catechol and guaiacol analogues at carbon fiber microdisk electrodes following laser and electrochemical activation procedures. Electroanalysis 11, 37– 46. 45. Hofbauer, M., Heineman, W. R., Kreishman, G. P., and Steckhan, E. (1999) Hydrophobic interaction of analytes with permselective poly(N-vinyl amide) films on electrodes. Anal. Chem. 71, 399 – 406. 46. Ferreira, V. S., Zanoni, M. V. B., and Fogg, A. G. (1999) Cathodic stripping voltammetric determination of ceftazidime with reactive accumulation at a poly-L-lysine modified hanging mercury drop electrode. Anal. Chim. Acta 384, 159 –166. 47. El-Maali, N. A. (2000) Voltammetric analysis of ceftazidime after preconcentration at various mercury and carbon electrodes: Application to sub-ppb level determination in urine samples. Talanta 51, 957–968. 48. Shubietah, R. M., Abu Zuhri, A. Z., and Fogg, A. G. (1999) Adsorptive stripping voltammetric determination of dimenhydrinate at a hanging mercury drop electrode. Mikrochim. Acta 130, 165–171. 49. Lu, T. W., and Sun, I. W. (2000) Determination of diquat at a Nafion film modified glassy carbon electrode using electrocatalytic voltammetry. Electroanalysis 12, 605– 609. 50. Arranz, A., Moreda, J. M., and Arranz, J. F. (2000) On-column amperometric detection in capillary electrophoresis with an improved high-voltage electric field decoupler. Mikrochim. Acta 134, 69 –75. 51. De Betono, S. F., Garcia, A. A., and Valentin, J. F. A. (1999) UV-spectrophotometry and square wave voltammetry at nafion-modified carbon-paste electrode for the determination of doxazosin in urine and formulations. J. Pharm. Biomed. Anal. 20, 621– 630. 52. Jacquinot, P., Hodgson, A. W. E., Muller, B., Wehrli, B., and Hauser, P. C. (1999) Amperometric detection of gaseous ethanol and acetaldehyde at low concentrations on an Au-Nafion electrode. Analyst 124, 871– 876. 53. Sabry, S. M., and Mahgoub, H. (1999) Voltammetric, spectrofluorimetric and spectrophotometric methods to determine flufenamic acid. J. Pharmac. Biomed. Anal. 21, 993–1001. 54. Honeychurch, K. C., Hart, J. P., and Cowell, D. C. (2000) Voltammetric behavior and trace determination of lead at a mercury-free screen-printed carbon electrode. Electroanalysis 12, 171–177. 55. Kinoshita, H., Miya, T., and Kamihira, S. (1999) Amperometric determination of glutathione in yeast extract using a membrane-covered phthalocyanine embedded carbon-paste electrode. Bunseki Kagaku 48, 117–120. 56. De Mattos, I. L., Melo, D., and Zagatto, E. A. G. (1999) Nickelchromium electrode as a detector in flow-injection amperometry: Determination of glycerol. Anal. Sci. 15, 537–541. 57. You, T. Y., Niu, L., Gui, J. Y., Dong, S. J., and Wang, E. K. (1999) Detection of hydrazine, methylhydrazine and isoniazid by capillary electrophoresis with a 4-pyridyl hydroquinone self-

12

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

LAWRENCE ET AL. assembled microdisk platinum electrode. J. Pharm. Biomed. Anal. 19, 231–237. Govaert, F., Temmerman, E., and Kiekens, P. (1999) Development of voltammetric sensors for the determination of sodium dithionite and indanthrene/indigo dyes in alkaline solutions. Anal. Chim. Acta 385, 307–314. Ferna´ ndez-Sa´ nchez, C., and Costa-Garcı´a, A. (2000) Voltammetric studies of indigo adsorbed on pre-treated carbon paste electrodes. Electrochem. Commun. 2, 743– 814. Belal, F., Al-Malaq, H. A., and Al-Majed, A. A. (2000) Voltammetric determination of isoxsuprine and fenoterol in dosage forms and biological fluids through nitrosation. J. Pharm. Biomed. Anal. 23, 1005–1015. Shih, Y., and Zen, J. M. (1999) Voltammetric determination of kojic acid in cosmetic bleaching products using a disposable screen-printed carbon electrode. Electroanalysis 11, 229 –233. Mao, Y. N., Hu, J. B., Li, Q. L., and Xue, P. (2000) Study of the electrochemical behavior of mitoxantrone and its determination at a Co-C modified ultramicroelectrode. Analyst 125, 2299 – 2302. Popa, E., Notsu, H., Miwa, T., Tryk, D. A., and Fujishima, A. (1999) Selective electrochemical detection of dopamine in the presence of ascorbic acid at anodized diamond thin film electrodes. Electrochem. Solid State Lett. 2, 49 –51. Lacroix, M., Bianco, P., and Lojou, E. (1999) Modified random assembly of microelectrodes for the selective electrochemical detection of dopamine. Electroanalysis 11, 1068 –1076. Yang, L. J., Yang, C. F., Peng, T. Z., Yang, H. S., Gao, C., and Liu, G. Q. (1999) Electrochemical behavior and in vivo determination of the neurotransmitter dopamine using sodium montmorillonite modifiedelectrodes. Electroanalysis 11, 438 – 442. Ju, H. X., Ni, J. G., Gong, Y., Chen, H. Y., and Leech, D. (1999) Electrocatalytical oxidation and determination of dopamine at redox polymer/nafion modified electrodes. Anal. Lett., 32, 2951– 2964. Zen, J. M., Ilangovan, G., and Jou, J. J. (1999) Square-wave voltammetric determination and ac impedance study of dopamine on preanodized perfluorosulfonated ionomer-coated glassy carbon electrodes. Anal. Chem. 71, 2797–2805. Strawbridge, S. M., Green, S. J., and Tucker, J. H. R. (2000) Electrochemical detection of catechol and dopamine as their phenylboronate ester derivatives. Chem. Commun. 2393–2394. Fang, C., Tang, X. R., and Zhou, X. Y. (1999) Preparation of poly(Malachite green) modified electrode and the determination of dopamine and ascorbic acid. Anal. Sci. 15, 41– 46. Ciszewski, A., and Milczarek, G. (1999) Polyeugenol-modified platinum electrode for selective detection of dopamine in the presence of ascorbic acid. Anal. Chem. 71, 1055–1061. Liu, Z. M., Niwa, O., Kurita, R., and Horiuchi, T. (2000) Modified microelectrodes and multivariate calibration for flow injection amperometric simultaneous determination of ascorbic acid, dopamine, epinephrine and dipyrone. J. Chromatogr. A 891, 149 –156. Cookeas, E. G., and Efstathiou, C. E. (2000) Flow injectionpulse amperometric detection of ephedrine at a cobalt phthalocyanine modified carbon paste electrode. Analyst 125, 1147– 1150. Ni, J. A., Ju, H. X., Chen, H. Y., and Leech, D. (1998) [Os(bpy) (2) (PVP) (10)Cl]Cl polymer and Nafion dual-film modified graphite electrode for the amperometric determination of trace amounts of norepinephrine. Analyst 123, 2895–2898. Furlanetto, S., Orlandini, S., Aldini, G., Gotti, R., Dreassi, E., and Pinzauti, S. (2000) Designing experiments to optimise and

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

validate the adsorptive stripping voltammetric determination of nimesulide. Anal. Chim. Acta 413, 229 –239. Chen, X. H., Ruan, C. M., Kong, J. L., and Deng, J. Q. (1999) Amperometric determination of nitrite based on reaction with 3-mercaptopropanoic acid. Anal. Chim. Acta 382, 189 –197. Davis, J., McKeegan, K. J., Cardosi, M. F., and Vaughan, D. H. (1999) Evaluation of phenolic assays for the detection of nitrite. Talanta 50, 103–112. Song, F. Y., Lee, F. S. C., and Shiu, K. K. (2000) Preconcentration and electrochemical determination of nitropyrene at electrochemically activated glassy carbon electrodes. Electroanalysis 12, 128 –133. Pontie, M., Bedioui, F., and Devynck, J. (1999) New composite modified carbon microfibers for sensitive and selective determination of physiologically relevant concentrations of nitric oxide in solution. Electroanalysis 11, 845– 850. Pontie, M., Lecture, H., and Bedioui, F. (1999) Improvement in the performance of a nickel complex-based electrochemical sensor for the detection of nitric oxide in solution. Sens. Actuat. B-Chem. 56, 1–5. Tang, X. R., Fang, C., Yao, B. Y., and Zhang, W. M. (1999) Determination of nitric oxide by glassy carbon electrodes modified with poly(neutral red). Microchem. J. 62, 377–385. Kitajima, A., Miyake, M., Kobayashi, T., Koyama, H., Ikeda, O., Kijima, K., Komura, T., Uno, A., and Yamatodani, A. (1999) Detection of nitric oxide with the iron (III) porphyrin doped nafion/glassy carbon electrode. Electrochemistry 67, 784 –788. Villeneuve, N., Bedioui, F., Voituriez, K., Avaro, S., and Vilaine, J. P. (1998) Electrochemical detection of nitric oxide production in perfused pig coronary artery: Comparison of the performances of two electrochemical sensors. J. Pharmacol. Toxicol. Methods 40, 95–100. Jin, J. Y., Miwa, T., Mao, L. Q., Tu, H. P., and Jin, L. T. (1999) Determination of nitric oxide with ultramicrosensors based on electropolymerized films of metal tetraaminophthalocyanines. Talanta 48, 1005–1011. Zhuiykov, S., Nakano, T., Kunimoto, A., Yamazoe, N., and Miura, N. (2001) Potentiometric NOx sensor based on stabilized zirconia and NiCr 2O 4 sensing electrode operating at high temperatures. Electrochem. Commun. 3, 97–101. Lu, T. H., and Sun, I. W. (2000) Electrocatalytic determination of paraquat using a nafion film coated glassy carbon electrode. Talanta 53, 443– 451. Xue, J., Ying, X. Y., Chen, J. S., Xian, Y. H., Jin, L. T., and Jin, J. (2000) Amperometric ultramicrosensors for peroxynitrite detection and its application toward single myocardial cells. Anal. Chem. 72, 5313–5321. Schwarz, J., and Kaden, H. (2000) Microarray electrodes for voltammetric and amperometric detection of organic pollutants. Fres. J. Anal. Chem. 367, 384 –387. De Carvalho, R. M., Mello, C., and Kubota, L. T. (2000) Simultaneous determination of phenol isomers in binary mixtures by differential pulse voltammetry using carbon fibre electrode and neural network with pruning as a multivariate calibration tool. Anal. Chim. Acta 420, 109 –121. Brenes, M., Garcia, A., Garcia, P., and Garrido, A. (2000) Rapid and complete extraction of phenols from olive oil and determination by means of a coulometric electrode array system. J. Agric. Food Chem. 48, 5178 –5183. Arranz, A., De Betono, S. F., Echevarria, C., Moreda, J. M., Cid, A., and Valentin, J. F. A. (1999) Resolving uncertainty in chemical speciation determinations. J. Pharm. Biomed. Anal. 21, 797– 807.

VOLTAMMETRIC ANALYSIS OF BIOLOGICAL COMPOUNDS 91. Gadzekpo, V. P. Y., Xiao, K. P., Aoki, H., Buhlmann, P., and Umezawa, Y. (1999) Voltammetric detection of the polycation protamine by the use of electrodes modified with self-assembled monolayers of thioctic acid. Anal. Chem. 71, 5109 –5118. 92. Popa, E., Kubota, Y., Tryk, D. A., and Fujishima, A. (2000) Selective voltammetric and amperometric detection of uric acid with oxidized diamond film electrodes. Anal. Chem. 72, 1724 – 1727. 93. Bravo, R., and Brajtertoth, A. (1999) A highly active carbon microdisk electrode surface for the determination of uric acid in physiological buffers. Chem. Anal. 44, 423– 434. 94. Brajter-Toth, A., Abou El-Nour, K., Cavalheiro, E. T., and Bravo, R. (2000) Nanostructured carbon fiber disk electrodes for sensitive determinations of adenosine and uric acid. Anal. Chem. 72, 1576 –1584. 95. Cavalheiro, E. T. G., and Brajtertoth, A. (1999) Amperometric determination of xanthine and hypoxanthine at carbon electrodes: Effect of surface activity and the instrumental parameters on the sensitivity and the limit of detection. J. Pharm. Biomed. Anal. 19, 217–230. 96. Wang, L. H. (2000) Simultaneous determination of retinal, retinol and retinoic acid (all-trans and 13-cis) in cosmetics and pharmaceuticals at electrodeposited metal electrodes. Anal. Chim. Acta 415, 193–200. 97. Alonso, M. A., Sanllorente, S., Sarabia, L. A., and Arcos, M. J. (2000) Optimization of the experimental parameters in the determination of rifamycin SV by adsorptive stripping voltammetry. Anal. Chim. Acta 405, 123–133. 98. Ahamad, R., Barek, J., Yusoff, A. R., Sinaga, S. M., and Zima, J. (2000) Determination of roxarsone using carbon paste and amberlite LA2 modified carbon paste electrodes. Electroanalysis 12, 1220 –1226. 99. Volikakis, G. J., and Efstathiou, C. E. (2000) Determination of rutin and other flavonoids by flow- injection/adsorptive stripping voltammetry using nujol-graphite and diphenylethergraphite paste electrodes. Talanta 51, 775–785. 100. Zapardiel, A., Bermejo, E., Perez, J. A., and Chicharro, M. (2000) Determination of s-triazines with copper and glassy carbon electrodes: Flow injection analysis of aziprotryne in water samples. Fres. J. Anal. Chem. 367, 461– 466. 101. Beigi, A. A. M., Teymouri, M., Bagheri, A., Tash, S. A., and Saraji, M. (1999) Determination of trace total sulfur in organic compounds by Raney nickel reduction with voltammetric detection. Anal. Chim. Acta 381, 117–127. 102. Navratil, T., and Novotny, L. (2000) Detection of bioactive surfactants in aqueous solutions on the basis of H 2O 2-voltammetry. Fres. J. Anal. Chem. 366, 249 –253. 103. Khodari, M. (1998) Voltammetric determination of the anticancer 1,2,3,4 tetrahydrocarbazol in serum and urine on Pt modified carbon paste electrode. Quim. Anal. 17, 217–220. 104. Tomcik, P., Krajcikova, M., Bustin, D., and Skacani, I. (2001) Determination of tetramethylthiuram disulfide on an interdigitated microelectrode array. Electrochem. Commun. 3, 191–194. 105. Zen, J. M., Yu, T. Y., and Shih, Y. (1999) Determination of theophylline in tea and drug formulation usinga Nafion(R)/ lead-ruthenium oxide pyrochlore chemically modifiedelectrode. Talanta 50, 635– 640. 106. Aboul-Kasim, E. (2000) Anodic adsorptive voltammetric determination of the vitamin B-1 (thiamine). J. Pharm. Biomed. Anal. 22, 1047–1054. 107. Pemberton, R. M., and Hart, J. P. (1999) Electrochemical behaviour of triclosan at a screen-printed carbon electrode and its voltammetric determination in toothpaste and mouth rinse products, Anal. Chim. Acta 390, 107–115.

13

108. Ferancova, A., Korgova, E., Miko, R., and Labuda, J. (2000) Determination of tricyclic antidepressants using a carbon paste electrode modified with beta-cyclodextrin. J. Electroanal. Chem. 492, 74 –77. 109. Luque, M., Luque-Perez, E., Rios, A., and Valcarcel, M. (2000) Supported liquid membranes for the determination of vanillin in food samples with amperometric detection. Anal. Chim. Acta 410, 127–134. 110. Agui, L., Lopezguzman, J. E., Gonzalezcortes, A., Yanezsedeno, P., and Pingarron, J. M. (1999) Analytical performance of cylindrical carbon fiber microelectrodes in low-permitivity organic solvents: Determination of vanillin in ethyl acetate. Anal. Chim. Acta 385, 241–248. 111. Wang, L. H. (2000) Determination of zinc pyrithione in hair care products on metal oxides modified carbon electrodes. Electroanalysis 12, 227–232. 112. Sodum, R. S., Akerkar, S. A., and Fiala, E. S. (2000) Determination of 3-nitrotyrosine by high-pressure liquid chromatography with a dual-mode electrochemical detector. Anal. Biochem. 280, 278 –285. 113. Shi, G. Y., Xu, F., Xue, J., and Jin, L. T. (1999) High performance liquid chromatography-electrochemical detection (HPLC-ECD) for the pharmacokinetic studies of acetaminophen with microdialysis. Electroanalysis 11, 432– 437. 114. Andersen, R., and Sorensen, A. (2000) Separation and determination of alditols and sugars by high-pH anion-exchange chromatography with pulsed amperometric detection. J. Chromatogr. A 897, 195–204. 115. Misiego, A. S., Gil, E. P., and Lomba, J. R. G. (2000) Determination of aliphatic amines by high performance liquid chromatography with amperometric detection after derivatization with phenylisothiocyanate. Electroanalysis 12, 459 – 464. 116. Auger, J., Boulay, R., Jaillais, B., and Delion-Vancassel, S. (2000) Analysis of biogenic amines by solid-phase microextraction and high-performance liquid chromatography with electrochemical detection. J. Chromatogr. A 870, 395– 403. 117. Casella, I. C., Gatta, M., and Cataldi, T. R. I. (2000) Amperometric determination of underivatized amino acids at a nickelmodified gold electrode by anion-exchange chromatography. J. Chromatogr. A 878, 57– 67. 118. Sato, K., Jin, J. Y., Takeuchi, T., Miwa, T., Takekoshi, Y., Kanno, S., and Kawase, S. (2000) Indirect amperometric detection of underivatized amino acids in microcolumn liquid chromatography with carbon film based ring- disk electrodes. Analyst 125, 1041–1043. 119. Sato, K., Takekoshi, Y., Kanno, S., Kawase, S., Jin, J. Y., Takeuchi, T., and Miwa, T. (1999) Plastic film ring-disk carbon electrodes for the indirect amperometric detection of underivatized amino acids in liquid chromatography. Anal. Sci. 15, 957– 961. 120. Zhang, S., Sun, W. L., Zhang, W., Qi, W. Y., Jin, L. T., Yamamoto, K., Tao, S. G., and Jin, J. Y. (1999) Determination of thio compounds by liquid chromatography with amperometric detection at a Nafion indium hexacyanoferrate film modified electrode. Anal. Chim. Acta 386, 21–30. 121. Cox, J. A., Holmstrom, S. D., and Tess, M. E. (2000) Oxidation at a sol-gel composite electrode doped with a dirhodium-substituted polyoxometalate for amperometric detection of peptides separated by HPLC. Talanta 52, 1081–1086. 122. Kaiser, K., and Benner, R. (2000) Determination of amino sugars in environmental samples with high salt content by high performance anion exchange chromatography and pulsed amperometric detection. Anal. Chem. 72, 2566 –2572.

14

LAWRENCE ET AL.

123. Riber, J., De La Fuente, C., Vazquez, M. D., Tascon, M. L., and Batanero, P. S. (2000) Electrochemical study of antioxidants at a polypyrrole electrode modified by a nickel phthalocyanine complex: Application to their HPLC separation and to their FIA system detections. Talanta 52, 241–252. 124. Ruiz, M. A., Garciamoreno, E., Barbas, C., and Pingarron, J. M. (1999) Determination of phenolic antioxidants by HPLC with amperometric detection at a nickel phthalocyanine polymer modified electrode. Electroanalysis 11, 470 – 474. 125. D’Eramo, F., Marioli, J. M., Arevalo, A. A., and Sereno, L. E. (1999) HPLC analysis of carbohydrates with electrochemical detection at a poly-1-naphthylamine/copper modified electrode. Electroanalysis 11, 481– 486. 126. Hanko, V. P., and Rohrer, J. S., (2000) Determination of carbohydrates, sugar alcohols, and glycols in cell cultures and fermentation broths using high-performance anion-exchange chromatography with pulsed amperometric detection. Anal. Biochem. 283, 192–199. 127. Cataldi, T. R. I., Margiotta, G., Iasi, L., Di Chio, B., Xiloyannis, C., and Bufo, S. A. (2000) Determination of sugar compounds in olive plant extracts by anion-exchange chromatography with pulsed amperometric detection. Anal. Chem. 72, 3902–3907. 128. Torto, N., Lobelo, B., and Gorton, L. (2000) Determination of saccharides in wastewater from the beverage industry by microdialysis sampling, microbore high performance anion exchange chromatography and integrated pulsed electrochemical detection. Analyst 125, 1379 –1381. 129. Bardotti, A., Ravenscroft, N., Ricci, S., D’Ascenzi, S., Guarnieri, V., Averani, G., and Constantino, P. (2000) Quantitative determination of saccharide in Haemophilus influenzae type b glycoconjugate vaccines, alone and in combination with DPT, by use of high-performance anion-exchange chromatography with pulsed amperometric detection. Vaccine 18, 1982–1993. 130. Yokota, H., Mori, K., Yamaguchi, H., Kaniwa, H., and Saisho, N. (1999) Monosaccharide composition analysis of pamiteplase by anion exchange chromatography with pulsed amperometric detection. J. Pharm. Biomed. Anal. 21, 767–774. 131. Kuo, C. T., and Chen, H. W. (2000) Determination of 1,3-, 1,6-, 1,8-dinitropyrene and 1-nitropyrene in airborne particulate by column liquid chromatography with electrochemical detection. J. Chromatogr. A 897, 393–397. 132. Carrero, H., and Rusling, J. F. (1999) Analysis of haloacetic acid mixtures by HPLC using an electrochemical detector coated with a surfactant-nafion film. Talanta 48, 711–718. 133. Kosminsky, L., and Bertotti, M. (1999) Determination of iodate in salt samples with amperometric detection at a molybdenum oxide modified electrode. Electroanalysis 11, 623– 626. 134. Cullison, J. K., Waraska, J., Buttaro, D. J., Acworth, I. N., and Bowers, M. L. (1999) Electrochemical detection of catecholamines at sub-5 fg levels by redox cycling. J. Pharm. Biomed. Anal. 19, 253–259. 135. Sagar, K. A., and Smyth, M. R. (2000) Bioavailability studies of oral dosage forms containing levodopa and carbidopa using column-switching chromatography followed by electrochemical detection. Analyst 125, 439 – 445. 136. Marazuela, M., Agui, L., Gonzalez-Cortes, A., Yanez-Sedeno, P., and Pingarron, J. (1999) Microcylinder polymer modified electrodes as amperometric detectors for liquid chromatographic analysis of catecholamines. Electroanalysis 11, 1333– 1339. 137. Lu, J. X., Zhang, S., Wang, A. B., Zhang, W., and Jin, L. T. (2000) In vivo monitoring of the monoamine neurotransmitters in the rat brain by microdialysis coupled with the liquid chro-

138.

139.

140.

141.

142.

143.

144.

145.

146.

147.

148.

149.

150.

151.

152.

153.

154.

matography dual electrochemical detector. Talanta 52, 807– 815. Sarada, B. V., Rao, T. N., Tryk, D. A., and Fujishima, A. (1999) Electrochemical detection of serotonin using conductive diamond electrodes. Chem. Lett. 1213–1214. Fu, C. G., Wang, L. X., and Fang, Y. Z. (1999) Determination of oxalic acid in urine by co-electroosmotic capillary electrophoresis with amperometric detection. Talanta 50, 953–958. Shen, H., Witowski, S. R., Boyd, B. W., and Kennedy, R. T. (1999) Detection of peptides by precolumn derivatization with biuret reagent and preconcentration on capillary liquid chromatography columns with electrochemical detection. Anal. Chem. 71, 987–994. Evans, O. (1999) On-line deoxygenation in reductive (and oxidative) amperometric detection: environmental applications in the liquid chromatography of organic peroxides. Analyst 124, 1811–1816. Pei, J. H., and Li, X. Y. (1999) Electrocatalysis and flow-injection analysis of hydrogen and organic peroxides at CuPtCl 6 chemically modified electrodes. Electroanalysis 11, 1211–1217. Wink, O., and Schack, F. (2000) Determination of superabsorbent polyacrylate dust in workplace atmospheres after derivatization with ethanol and using HPLC with pulsed electrochemical detection. Analyst 125, 1745–1750. Zhu, Y. X., Huang, T. H., Cregor, M., Long, H., Kissinger, C. B., and Kissinger, P. T. (2000) Liquid chromatography with multichannel electrochemical detection for the determination of trans-resveratrol in rat blood utilizing an automated blood sampling device. J. Chromatogr. B 740, 129 –133. Rao, T. N., Sarada, B. V., Tryk, D. A., and Fujishima, A. (2000) Electroanalytical study of sulfa drugs at diamond electrodes and their determination by HPLC with amperometric detection. J. Electroanal. Chem. 491, 175. Lacourse, W. R., and Dasenbrock, C. O. (1999) Pulsed electrochemical detection of sulfur-containing antibiotics following high performance liquid chromatography. J. Pharm. Biomed. Anal. 19, 239 –252. Popovic, N. D., and Johnson, D. C. (1999) Amperometric detection of biologically significant sulfur-containing compounds at Bi(V)-doped PbO 2 film electrodes. Electroanalysis 11, 934 –939. Szunyog, J., Adams, E., Roets, E., and Hoogmartens, J. (2000) Analysis of tobramycin by liquid chromatography with pulsed electrochemical detection. J. Pharm. Biomed. Anal. 23, 891– 896. Wang, J., Chatrathi, M. P., and Tian, B. M. (2000) Micromachined separation chips with a precolumn reactor and endcolumn electrochemical detector. Anal. Chem. 72, 5774 –5778. Holland, L. A., and Lunte, S. M. (1999) Postcolumn reaction detection with dual-electrode capillary electrophoresis-electrochemistry and electrogenerated bromine. Anal. Chem. 71, 407– 412. Zhong, M., and Lunte, S. M. (1999) Tubular-wire dual electrode for detection of thiols and disulfides by capillary electrophoresis/electrochemistry. Anal. Chem. 71, 251–255. Hua, L., Chia, L. S., Goh, N. K., and Tan, S. N. (2000) Amperometric detection of carbohydrates by capillary electrophoresis with a cuprous oxide modified sol-gel carbon composite electrode. Electroanalysis 12, 287–291. Fu, C. G., and Fang, Z. L. (2000) Combination of flow injection with capillary electrophoresis. 7. Microchip capillary electrophoresis system with flow injection sample introduction and amperometric detection. Anal. Chim. Acta 422, 71–79. Jin, W. R., Xu, Q., and Li, W. (2000) Determination of clozapine by capillary zone electrophoresis following end-column amperometric detection with simplified capillary/electrode alignment. Electrophoresis 21, 1415–1420.

VOLTAMMETRIC ANALYSIS OF BIOLOGICAL COMPOUNDS 155. Zhou, J. K., Chen, Y., and Cassidy, R. (2000) Separation and determination of the macrolide antibiotics (erythromycin, spiramycin and oleandomycin) by capillary electrophoresis coupled with fast reductive voltammetric detection. Electrophoresis 21, 1349 –1353. 156. Matysik, F. M., Bjorefors, F., and Nyholm, L. (1999) Application of microband array electrodes for end-column electrochemical detection in capillary electrophoresis. Anal. Chim. Acta 385, 409 – 415. 157. Jin, W. R., Dong, Q., Ye, X. Y., and Yu, D. Q. (2000) Assay of glutathione in individual mouse peritoneal macrophages by capillary zone electrophoresis with electrochemical detection. Anal. Biochem. 285, 255–259. 158. Wang, J., Chatrathi, M. P., Tian, B. M., and Polsky, R. (2000) Capillary electrophoresis chips with thick-film amperometric detectors: Separation and detection of hydrazine compounds. Electroanalysis 12, 691– 694. 159. Backofen, U., Matysik, F. M., Hoffmann, W., and Lunte, C. E. (2000) Analysis of illicit drugs by nonaqueous capillary electrophoresis and electrochemical detection. Fres. J. Anal. Chem. 367, 359 –363. 160. Wang, J., Tian, B. M., and Sahlin, E. (1999) Integrated electrophoresis chips/amperometric detection with sputtered gold working electrodes. Anal. Chem. 71, 3901–3904. 161. Chen, D. C., Chang, S. S., and Chen, C. H. (1999) Parallelopposed dual-electrode detector with recycling amperometric enhancement for capillary electrophoresis. Anal. Chem. 71, 3200 –3205. 162. Wang, J., Tian, B. M., and Sahlin, E. (1999) Micromachined electrophoresis chips with thick-film electrochemical detectors. Anal. Chem. 71, 5436 –5440. 163. Liu, Z. M., Niwa, O., Kurita, R., and Horiuchi, T. (2000) Carbon film-based interdigitated array microelectrode used in capillary electrophoresis with electrochemical detection. Anal. Chem. 72, 1315–1321. 164. Hua, L., and Tan, S. N. (2000) Amperometric detection for capillary electrophoresis at a sol-gel carbon composite electrode. Anal. Chim. Acta 403, 179 –186. 165. Zhang, S. S., Yuan, Z. B., Liu, H. X., Zou, H., and Wu, Y. J. (2000) On-column amperometric detection in capillary electrophoresis with an improved high-voltage electric field decoupler. J. Chromatogr. A 872, 259 –268. 166. Wang, J., Chatrathi, M. P., and Tian, B. M. (2000) Capillary electrophoresis microchips with thick-film amperometric detectors: Separation and detection of phenolic compounds. Anal. Chim. Acta 416, 9 –14. 167. Luong, J. H. T., Hilmi, A., and Nguyen, A. L. (1999) Nonaqueous capillary electrophoresis equipped with amperometric detection for analysis of chlorinated phenolic compounds. J. Chromatogr. A 864, 323–333. 168. Jin, W. R., Yu, D. Q., Dong, Q., and Ye, X. Y. (2000) A new method of quantification of pipemidic acid by capillary zone electrophoresis with end-column amperometric detection. Electrophoresis 21, 925–929. 169. Yang, W. C., Yu, A. M., Dai, Y. Q., and Chen, H. Y. (2000) Separation and determination of di- and tricarboxylic acids in fruits by capillary zone electrophoresis with amperometric detection. Anal. Chim. Acta 415, 75– 81. 170. Wang, A. B., Li, L. J., Zang, F., and Fang, Y. Z. (2000) Amperometric detection of three purine alkaloids following their separation by micellar electrokinetic capillary chromatography. Anal. Chim. Acta 419, 235–242. 171. Jin, W. R., Ye, X. Y., Yu, D. Q., and Dong, Q. (2000) A simple capillary zone electrophoretic assay for reserpin using end-

172.

173.

174. 175.

176.

177. 178.

179.

180.

181.

182.

183.

184.

185.

186.

187. 188.

189.

190.

15

column amperometric detection at a carbon fiber micro-disk array electrode. Anal. Chim. Acta 408, 257–262. Wang, A., Zhang, L., Zhang, S., and Fang, Y. (2000) Determination of thiols following their separation by CZE with amperometric detection at a carbon electrode. J. Pharm. Biomed. Anal. 23, 429 – 436. Hu, S., Zhang, M., Pang, D. W., and Cheng, J. K. (2000) Powder microelectrodes for capillary electrophoresis with amperometric detection. Anal. Sci. 16, 807– 810. Zuman, P. (2000) Role of mercury electrodes in contemporary analytical chemistry. Electroanalysis 12, 1187–1194. Ratcliffe, H. E., Swanson, G. M., and Fischer, L. J. (1996) Human exposure to mercury: A critical assessment of the evidence of adverse health effects. J. Toxicol. Environ. Health 49, 221–270. Micaroni, R. C. D. M., Bueno, M. I. M. S., and Jardim, W. D. (2000) Mercury compounds: Review on determination, treatment and disposal methods. Quim. Nova 23, 487– 495. Kok, W., Brinkman, U., and Frei, R. (1983) J. Chromatogr. 256, 17–26. Engstromsilverman, C. E., and Ewing, A. G. (1991) Copper wire amperometric detector for capillary electrophoresis. J. Microcolumn Sep. 3, 141–145. Stulik, K., Pacakova, V., Le, K., and Hennissen, B. (1988) Amperometric flow detection with a copper working electrode response mechanism and application to various compounds. Talanta 35, 455– 460. Ye, J. N., and Baldwin, R. P. (1994) Determination of amino-acids and peptides by capillary electrophoresis and electrochemical detection at a copper electrode. Anal. Chem. 66, 2669 –2674. Luo, P. F., Zhang, F. Z., and Baldwin, R. P. (1991) Constant potential amperometric detection of underivatized amino-acids and peptides at a copper electrode. Anal. Chem. 62, 752–755. Xie, Y. Q., and Huber, C. O. (1991) Electrocatalysis and amperometric detection using an electrode made of copper-oxide and carbon paste. Anal. Chem. 63, 1714 –1719. Prabhu, S., and Baldwin, R. P. (1989) Electrocatalysis and detection of amino-sugars, alditols, and acidic sugars at a copper-containing chemically modified electrode. Anal. Chem. 61, 2258 –2263. Colon, L. A., Dadoo, R., and Zare, R. N. (1993) Determination of carbohydrates by capillary zone electrophoresis with amperometric detection at a copper microelectrode. Anal. Chem. 65, 476 – 481. Sato, K., Jin, J. Y., Takeuchi, T., Miwa, T., Takekoshi, Y., Kanno, S., and Kawase, S. (2001) Nickel-titanium alloy electrodes for stable amperometric detection of underivatized amino acids in anion-exchange chromatography. Talanta 53, 1037–1044. Moorcroft, M. J., Nei, L., Davis, J., and Compton, R. G. (2000) Enhanced electrochemical detection of nitrite and nitrate at a Cu-30Ni alloy electrode. Anal. Lett. 33, 3127–3137. Gorton, L. (1995) Carbon paste electrodes modified with enzymes, tissues and cells. Electroanalysis 7, 23– 45. Kalcher, K., Kauffmann, J. M., Wang, J., Svancara, I., Vytras, K., Neuhold, C., and Yang, Z. (1995) Sensors based on carbon paste in electrochemical analysis: A review with particular emphasis on the period 1990 –1993. Electroanalysis 7, 5–22. Walcarius, A. (1998) Analytical applications of silica modified electrodes—A comprehensive review. Electroanalysis 10, 1217– 1235. Diamond, D. (1993) Progress in sensor array research. Electroanalysis 5, 795– 802.

16

LAWRENCE ET AL.

191. Niwa, O. (1995) Electroanalysis with interdigitated array microelectrodes. Electroanalysis 7, 606 – 613. 192. Linder, E., Cosofret, V. V., Buck, R. P., Johnson, T. A., Ash, R. B., Neuman, M. R., Kao, W. J., and Anderson, J. M. (1995) Electroanalytical and biocompatibility studies on microfabricated array sensors. Electroanalysis 7, 864 – 870. 193. Fletcher, S., and Horne, M. D. (1999) Randon assemblies of microelectrodes (RAM electrodes) for electrochemical studies. Electrochem. Commun. 1, 502–512. 194. March, J. (1992) Advanced Organic Chemistry, 4th ed., Wiley, New York. 195. Mattila, P., Lehtonen, M., and Kumpulainen, J. (2000) Comparison of in-line connected diode array and electrochemical detectors in the high-performance liquid chromatographic analysis of coenzymes Q(9) and Q(10) in food materials. J. Agric. Food Chem. 48, 1229 –1233. 196. Inoue, K., Kato, K., Yoshimura, Y., Makino, T., and Nakazawa, H. (2000) Determination of bisphenol A in human serum by high-performance liquid chromatography with multi-electrode electrochemical detection. J. Chromatogr. B 749, 17–23. 197. Jorgenson, J. W., and Wit, J. D. (1992) in Detectors for Capillary Chromatography (Hill, H. H., and McMinn, D. G., Eds.), Vol. 121, pp. 395– 425, Wiley, New York. 198. Bryant, B. R., Swanek, F. D., and Ewing, A. G. (1998) in High Performance Capillary Electrophoresis (Khaledi, M. G., Ed,), Vol. 146, pp. 355–374, Wiley, New York.

199. Kappes, T., and Hauser, P. C. (2000) Recent developments in electrochemical detection methods for capillary electrophoresis. Electroanalysis 12, 165–170. 200. Compton, R. G., Eklund, J. C., and Marken, F. (1997) Sonoelectrochemical processes: A review. Electroanalysis 9, 509 –522. 201. Ball, J. C., and Compton, R. G. (1999) Application of ultrasound to electrochemical measurements and analyses. Electrochemistry 67, 912–919. 202. Akkermans, R. P., Wu, M., and Compton, R. G. (1998) A comparison between pulsed sonovoltammetry and low power laser activated voltammetry for the electroanalysis of ascorbic acid in a commercial fruit drink. Electroanalysis 10, 814 – 820. 203. Beckett, E. L., Lawrence, N. S., Tsai, Y. C., Davis, J., and Compton, R. G. (2001) Bioanalytical utility of sonovoltammetry. J. Pharmaceut. Biomed. Anal. 26, 995–1001. 204. Beckett, E. L., Lawrence, N. S., Evans, R. G., Davis, J., and Compton, R. G. (2001) Sonoelectrochemically enhanced determination of 5-aminosalicylic acid. Talanta 54, 871– 877. 205. Bulska, E. (2001) Analytical advantages of using electrochemistry for atomic spectrometry. Pure Appl. Chem. 73, 1–7. 206. Pretty, J. R., Deng, H., Goeringer, D. E., and Van Berkel, G. J. (2000) Electrochemically modulated preconcentration and matrix elimination for organic analytes coupled on-line with electrospray mass spectrometry. Anal. Chem. 72, 2066 – 2074.