MASS SPECTROMETRIC DETECTION OF TRACE ANIONS: THE EVOLUTION OF PAIRED-ION ELECTROSPRAY IONIZATION (PIESI) Zachary S. Breitbach,1 Alain Berthod,2 Ke Huang,1 and Daniel W. Armstrong1* 1

Department of Chemistry, University of Texas at Arlington, Planetarium Place, Arlington 76019, Texas 2 Institute of Analytical Sciences, University of Lyon, 5 rue de la Doua, Villeurbanne 69100, France

Published online 3 February 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mas.21448

The negative-ion mode of electrospray ionization mass spectrometry (ESI-MS) is intrinsically less sensitive than the positive-ion mode. The detection and quantitation of anions can be performed in positive-ion mode by forming specific ion-pairs during the electrospray process. The paired-ion electrospray ionization (PIESI) method uses specially synthesized multifunctional cations to form positively charged adducts with the anions to be analyzed. The adducts are detected in the positive-ion mode and at higher m/z ratios to produce excellent signal-tonoise ratios and limits of detection that often are orders of magnitude better than those obtained with native anions in the negative-ion mode. This review briefly summarizes the different analytical approaches to detect and separate anions. It focuses on the recently introduced PIESI method to present the most effective dicationic, tricationic, and tetracationic reagents for the detection of singly and multiply charged anions and some zwitterions. The mechanism by which specific structural molecular architectures can have profound effects on signal intensities is also addressed. # 2015 Wiley Periodicals, Inc. Mass Spec Rev 35:201–218, 2016.

Blount & Valentin-Blazini, 2006; Sottani & Minoia, 2002; Ghanem et al., 2007; Tsikas, 2004; Yamashita et al., 2004). Paired-ion electrospray ionization (PIESI) is a recently developed innovative approach for ultra-trace detection of anions in the positive-ion ESI-MS mode (Soukup-Hein et al., 2007; Breitbach et al., 2008; Remsburg et al., 2008; Warnke et al., 2009a; Zhang et al., 2010). PIESI introduces very low concentrations of a multicharged cation (the ion pairing agent [IPR]) in its F
or OH
form into the sample stream. The IPR/anion complex is detected in positive-ion ESI-MS with very excellent limits of detection (LOD). PIESI can be used as a detection process with or without an ion separation technique such as ion chromatography, reversed-phase LC, or capillary electrophoresis (Gerardi et al., 2012; Xu & Armstrong, 2013). This review will list the different methods for anion determination and focuses on separation and detection methods. The PIESI method will be described in detail to compare it with other anion-detection methods and to focus on the reasons for signal enhancements that result in exceptional LODs for many anions.

Keywords: paired-ion electrospray ionization mass spectrometry (PIESI-MS); ion-pairing reagents; anion detection; sensitivity; chromatography

II. ANION-SEPARATION METHODS

I. INTRODUCTION The development and use of a variety of methods for the trace analysis of anions in widely different samples has a long and distinguished history (Boltz, 1973). Anions are routinely determined in environmental samples such as seawater (Yamashita et al., 2004), surface water (Hansen et al., 2002; Le, Lu, & Li, 2004), ground water (Barron & Paull, 2006), biological samples, such as urine (Mandal, Ogra, & Suzui, 2001; Tsikas, 2004), serum (Sottani & Minoia, 2002), amniotic fluid (Blount & Valentin-Blazini, 2006), or other samples such as food (Dyke et al., 2006) or sewage sludge (Ghanem et al., 2007). Mass spectrometry (MS) is a method of choice for sensitive ion analyses of cations as well as anions (Barron & Paull, 2006;

 Correspondence to: Professor Daniel W. Armstrong, The University of Texas at Arlington, Department of Chemistry and Biochemistry, 700 Planetarium Place, Arlington, 76019, TX. E-mail: [email protected]

Mass Spectrometry Reviews, 2016, 35, 201–218 # 2015 by Wiley Periodicals, Inc.

Most samples do not contain a single type of anion. For accurate anion analysis, it is often necessary to separate sample components when challenging matrices are being interrogated. A number of analytical techniques can be used to separate and measure anionic content in samples.

A. Liquid Chromatography The most-advanced analytical method for ion separation is ion chromatography (IC). IC is a form of liquid chromatography that separates cations or anions based on differences in affinities between the analyte ions in the mobile phase and the ion-exchange stationary phase. IC is a highly mature state-of-the-art technique supported by well-developed hardware, a strong user base, and well-established fundamental theories. The breakthrough in IC occurred in 1975 when Small et al. described a low-capacity pellicular-based new resin stationary phase that led to columns that could separate ions with a high peak efficiency (narrow peaks). They coupled the column with a chemical suppressor column followed by a conductivity detector (Small, Stevens, & Bauman, 1975). To date, IC is the most-evolved and most-

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practiced analytical technique to determine ion compositions in aqueous samples. Modern IC is a fast and efficient technique with a part-per-billion detection limit (mg/L), high selectivity and sensitivity, and very low sample consumption. It can be used for charged species that range from simple inorganic anions or cations to proteins. Anions must be separated with anion-exchange columns and cations with cation-exchange columns. Recently, zwitterionic resins were developed for the simultaneous separation of positively and negatively charged species. Reference books and reviews on IC include Haddad & Jackson, 1990; Dasgupta, 1992; Nesterenko, Nesterenko, & Paull B, 2009; Fritz et al., 2009 or Weiss, 2004. High performance liquid chromatography (HPLC) is the most widely used modern separation technique. For anion separation, reverse-phase liquid chromatography (RPLC) is most-frequently used. With appropriate buffer, pH adjustments, and often the addition of monovalent, alkyl substituted ion-pairing agents to the mobile phase, many organic anions and some inorganic anions can be separated with common C18 columns and have been detected at 75 ppb (or mg/L) with conductivity detection (Yan et al., 2003). Many different ion-pairing reagents can be added to the hydroorganic mobile phase (Tamosiunas, Padarauskas, & Pranaityte, 2006; Petritis et al., 1999), however, such ionpairing agents typically suppress ESI-MS signals. Also, some ions can be derivatized to allow RPLC separations with C18 columns (Small & Hintelmann, 2007). Specialty columns to separate mixed samples with ionic and molecular species can be obtained as well (Luo et al., 2008; Major, 2013). Recently, hydrophilic interaction liquid chromatography (HILIC) separated anions with cyclofructan-based and zwitterionic stationary phases (Qiu et al., 2011; Qiu, Armstrong, & Berthod, 2013; Padivitage, Dissanayake, & Armstrong, 2013). Thin-layer chromatography (TLC) does not receive all the attention it deserves because it is so simple that it does not require intricate instrumentation. However, it should not be overlooked for separation of anions because it has significant advantages as an analytical technique: (i) it is simple and costefficient; (ii) it is easy to set-up and operate; (iii) twodimensional separations can be easily performed simply by changing the mobile phase and rotating the plate 90˚; (iv) separated compounds are always detected in the “whole column”; (v) TLC is practically applicable for any type of sample (Srivastava, 2010). Drawbacks of TLC are poor detection sensitivity, mediocre accuracy, and low precision. Still, due to its simplicity TLC is a commonly used technique for anion separation (Kato et al., 2002), product examination, and reaction monitoring by organic chemists (Chernestova & Morlock, 2011).

B. Capillary Electrophoresis Capillary electrophoresis (CE) gained its popularity in ion analysis since its inception as a means of inorganic anion separation in 1990 (Ahuja & Jimidar, 2008). Ions are separated in CE based on their electrophoretic mobilities. Compared to ion chromatography, CE offers higher speed, at least 10-times greater separation efficiencies, and often different selectivities (Haddad, 1997; Harakuwe & Haddad, 2001). Also, CE is more tolerant to sample-matrix variances and more amenable to 202

simultaneous detection of cations and anions (Jackson & Haddad, 1993). However, CE has been perceived to suffer from poor reproducibility, low precision, difficult method development, and limitations in the choice of detectors. Although at a less-developed stage than IC, CE has been a lively area of scientific attention and research for separation of anions (Evenhuis et al., 2004; Timerbaev, 2008; Krizek et al., 2009; Feng et al., 2012).

C. Gas Chromatography Gas chromatography (GC) must be mentioned because it can be used to separate certain anions (e.g., carboxylates) when properly derivatized. Several derivatizaton techniques were developed to enhance anion volatility. Anion alkylation (D’Ulivo et al., 2009), pentafluorobenzoylation (Palit et al., 2004), or silylation (Purdon, Pagotto, & Miller, 1989) are examples of derivatization reactions used for anion analyses with GC. The strong point of GC is the universal and sensitive flame ionization detector (FID) that detects all carbon-containing solutes, including derivatized organic anions. GC-MS can also be used for compound structural identifications. GC is a fast and highly efficient technique; however, for anion analysis, it has a limited scope, and the necessity for sample derivatization introduces inevitable complications in the methodology.

D. Ion Mobility Spectrometry Ion-mobility spectrometry (IMS) is a gas-phase electrophoretic technique that separates ions on the basis of their mobility in a carrier buffer gas (Eiceman & Karpas, 2005). IMS has a range of advantages, including high speed (milliseconds to seconds), high sensitivity, and moderate cost. These qualities explain the extensive use of IMS in airport security devices (National Research Council, 2004), military and related security screening (Lee, 2012), and portable instruments for environmental monitoring (Eiceman & Karpas, 2005). As a laboratory technique in petroleum or pharmaceutical industries, IMS is an important technique to evaluate cleaning processes for manufacturing equipment (Strege et al., 2008), quality assessment (Vautz et al., 2006) and chemical monitoring (Eiceman & Karpas, 2005). From a fundamental point of view, IMS could be considered a detection as well as a separation system.

III. ANION-DETECTION TECHNIQUES Anions separated by any means must be detected to be identified and quantified. This is the purpose of the detection system. Anions have at least one negative charge, that can be used for detection with conductivity, oxidation-reductive properties, or potentiometry. Some anions also have a chromophore to allow spectrophotometric detection. This review focuses on mass spectrometric detection of both organic and inorganic anions.

A. Conductivity Conductivity uses the electrical conductivity change induced by the presence of ions (Buchberger, 2001). It is the major detector for IC. Conductivity and CE are also coupled for the analysis of anions, though it is somewhat more challenging due to the Mass Spectrometry Reviews DOI 10.1002/mas

ANION DETECTION BY ESI AND PIESI

electrophoretic fluid inside the capillary which contains an electrolyte (Huang et al., 1989). Contactless conductivity detection devices can be used with CE because they are easily implemented and very robust (Zemann et al., 1998).

B. Electroanalytical Reaction Techniques that use electrochemical reactions are voltammetry, potentiometry (De Backer & Nagel, 1996), and coulometry (Wang, 2002). They can be used to detect electroactive anions as well as cations (Tanyanywa, Leuthardt, & Hauser, 2002). Electroanalytical detection methods are mainly coupled with RPLC and CE for organic or inorganic non-UV absorbing anions (e.g., organic: acetate, citrate, lactate, succinate, or tartarate; or inorganic: iodide, bromide, cyanide, sulfate, and thiosulfate) (Buchberger & Haddad, 1997). Electroanalytical methods offer high sensitivity, high selectivity, good LODs, and a wide linear range at modest cost. The problem is that solution-based electroactive anions are not as common as inactive ones. Derivatization of solutes to be analyzed with electroactive groups prior to the separation or post-column reactions are possible. There are many occasions where these sample treatments can be used with electrochemical detection to reach mg/L (ppb) concentration level (Fedorowski & Lacourse, 2010).

C. Ion-Selective Electrodes An ion-selective electrode (ISE) contains a high-selectivity sensor to convert chemical activity of a specific ion in solution to electrical potential. ISEs are widely used for quick and easy ion monitoring (Solsky, 1990). The most common ISE is the pH electrode, which is one of the most-common pieces of equipment in analytical laboratories. Miniaturized electrodes are associated with LC and CE separation techniques as selective detectors. ISEs have been used for inorganic anion detection in environmental samples (Vaireanu, 2005; Kim, Sudduth, & Hummel, 2009a), pharmaceutical or cosmetic analyses (Lenik, Wardak, & Marczewska, 2006; Wang & Chin, 2007), agriculture and fishery samples (Kim, Sudduth, & Hummel, 2009a; DeMarco & Phan, 2003), or in the food and beverage industry (Kulapina & Barinova, 1997). It must be noted that ISEs are inexpensive, portable, and simple to use. However, they suffer from serious practical difficulties in quantitation. They are frequently prone to interferences from accompanying ions, and have a response that depends on ionic strength, which may cause with drift between assays. Also, ISE specificity might be a drawback: a different electrode is needed for each different type of anion.

D. UV-Visible Detection Optical absorbance detection was one of the earliest established approaches for anion analysis (Buchberger, 2001). Direct UVvis detection is sensitive and selective for the assays of compounds with sufficient molar absorptivity in the working wavelength range. However, indirect absorbance detection is a more universal technique with a wider applicability for non-light absorbing anions. For example, organic anions of carboxylic acids as well as inorganic anions that lack a chromophore (halides, nitrate, sulfate, thiosulfate, phosphate) have been Mass Spectrometry Reviews DOI 10.1002/mas

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analyzed in a methylene blue-containing mobile phase (Doble & Haddad, 1999; Timerbaev et al., 2000). Evaporative light-scattering detection (ELSD) can be considered as a detection method that uses UV-visible light. The principle of the technique is to nebulize the mobile phase at the column exit and to dry the spray in a heated chamber. All volatiles are eliminated, and only dried solids remain in suspension in the gas phase. This process produces a signal as the particles pass through a laser beam and scatter the light (which is detected).

E. Mass Spectrometry Detection Mass spectrometry is the detector of choice for anions separated with different techniques such as LC or CE (Soga et al., 2002). MS fulfils all the requirements for a viable anion detection device. It is theoretically responsive to all anions. Yet, it is also a specific detector because it can differentiate anions. A wide variety of ion-generation sources and techniques exist; but, due to the prevalence of electrospray ionization (ESI) in research laboratories, this review will focus mainly on the use of this ionization source. First, an overview of other less-commonly employed ionization techniques, that have been used to determine anions, will be outlined. The torch of an inductively coupled plasma (ICP) has been coupled with a mass spectrometer since 1983. ICP-MS has gained popularity, mainly for its sensitivity to detect trace amounts of metals in the ppt (or ng/L or pg/g) range. Also, the high-temperature plasma-ionization source often decreases matrix interferences to allow analyses of a variety of difficultto-analyze samples. Another result of ICP ionization is formation of only cationic species. For this reason, elements that exist only as anions (e.g., halides) are typically not detected with ICP-MS. Yet, there are a number of anionic metal complexes and other inorganic anions (e.g., arsenate anions) that are routinely determined with ICP-MS (Tanner, Baranov, & Bandura, 1999). Bromate and iodate in water samples, as well as sulfide, sulfate, sulfite, and thiocyanate present in biological assays, have been detected with ICP-MS (Divjak & Goessler, 1999; Divjak, Novicˇ, & Goessler, 1999). It is important to note, that for all anionic species determined with ICP-MS, the actual detected ion is cationic. For example, in the detection of sulfide, sulfate, sulfite, and thiocyanate, the same 32 16 þ S O ion is detected for each sulfur-containing anion (Divjak & Goessler, 1999). Hence, there is no way for a standalone ICP-MS to offer speciation information for anions that possess the same element. Thus, ICP-MS is routinely coupled with HPLC or IC to separate species prior to ionization (Popp, Hann, & Koellensperger, 2010). Matrix-assisted laser desorption/ionization (MALDI) is a soft-ionization technique in which a laser beam ablates an absorptive matrix, that in turn ionizes analytes (which are dissolved and/or co-crystallized) in the matrix in an ion plume. Typically, MALDI is used to evaluate large polymers and biomacromolecules with time-of-flight (TOF) MS. A major reason for the lack of MALDI as a tool to analyze low molecular weight anions is that the typical matrices used are composed of low molecular weight anionic compounds (i.e., dihydroxybenzoic acid, sinapinic acid, ferulic acid, picolinic acid, etc.) often with added trifluoroacetic acid. The matrix and its fragments dominate the low-mass region to create a high background that 203

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hinders small-ion detection. Nonetheless, there are a few examples of negative-ion MALDI detection of anions of oligonucleotides (Mengel-Jørgensen et al., 2004), phospholipids (Shanta et al., 2011), and anionic complexes of oligosaccharides (Cai, Jiang, & Cole, 2003). It should be noted that a similar technique, laserinduced liquid beam ionization/desorption (LILBID), does not require addition of a matrix to aqueous solutions, and it has been used in the negative-ion mode (Wattenberg, Sobott, & Brutschy, 2000). Due to the absence of low molecular weight background interferences, that typically arise from MALDI matrices, LILBID is more suited toward small molecular weight anions than MALDI. Electron ionization (EI) and chemical ionization (CI) are the two dominant ionization sources that are coupled with GC. CI is a softer ionization process than EI. In EI, electrons are produced from a hot filament and interact with, and ionize, gasphase analyte molecules. In CI, analyte ions are produced by reacting with abundant ions of a reagent gas. The use of these two ionization sources for anion analysis is very limited due to the non-volatile nature of anionic analytes – unless they are derivatized. There are a few examples noted in the GCseparations section (vide supra). A handful of other MS ionization sources have been applied to the analysis of anions, though they are less commonly used than ESI. Atmospheric pressure chemical ionization (APCI) and atmospheric pressure photoionization (APPI) are useful ionization sources that are used in place of ESI when ESI does not ionize the analyte of interest well. Generally, that is not the case with polar anionic compounds that ionize well in ESI. APCI and APPI are often applied towards less-polar compounds. Also, in some cases, APCI and APPI might be less-affected by matrix interferences. Kauppila et al. showed that APCI and APPI can be used to form anions of neutral compounds (Kauppila et al., 2004), whereas Draper et al. utilized APCI to ionize dialkyl phosphates (Draper, Behniwal, & Wijekoon, 2008). Fast-atom bombardment (FAB) has been used in the negative-ionization mode to identify and profile anionic phospholipids in bacteria (Heller et al., 1987). Cody et al. developed direct analysis in real time (DART) to detect anionic indicators of explosives (Cody, Laramee, & Dupont Durst). They also applied DART to the detection of gamma-hydroxybutyric acid in gin (Cody, Laramee, & Dupont Durst). Tam and Hill used secondary electrospray ionization (SESI) to detect nitrates as explosive indicators (Tam & Hill, 2004), and Na et al. and Takats et al. used direct barrier discharge ionization (DBDI) and desorptive electrospray ionization (DESI), respectively, for trace-level detection of explosives through anion detection (Na et al., 2007; Taka´ts et al., 2005).

IV. ELECTROSPRAY IONIZATION MASS SPECTROMETRY A. Electrospray Ionization Electrospray ionization (ESI) allows introduction of small to large, non-volatile molecules in a MS directly from the liquid phase. ESI is ideally suited for HPLC and CE coupling (Fenn et al., 1989; Cech & Enke, 2001). The ESI principle is: the eluent from the separation device (or simply infused into the MS) should have a flow rate between 204

1 mL/min and 1 mL/min in a capillary tube. The open end of the tube is opposite a small orifice which is the sample entry into the mass spectrometer. A positive (positive-ion mode) or negative (negative-ion mode) voltage (between 2 and 5 kV) is applied to the capillary relative to the metal forming the entrance orifice. The electric field produced by the high voltage produces a distortion of the liquid at the capillary outlet, referred to as the “Taylor cone”, and droplets that contain an excess of positive (or negative, depending on the applied voltage) charges are expelled from the capillary. The charged droplets are accelerated by electrical fields and move towards the orifice while quickly evaporating. Dry ions are eventually obtained and enter the MS through a pinhole in the counter-electrode (Cech & Enke, 2001). This description of the ESI ion production is greatly simplified (Fig. 1). A recent review described the complicated reactions that occur from solutes or ions in solution to ions in the gas phase (Kebarle & Verkerk, 2009). The reader is directed to this review for a more-detailed description of this process.

B. Anion Detection In The Negative Ion Mode ESI The negative-ion mode is well-suited for many ESI applications when very low quantity LODs are not required. Typically, organic anions that contain acidic functional groups (i.e., carboxylates, sulfates, sulfonates, and phosphates) are generally well-ionized in the negative-ion mode. Nowadays, many mass spectrometers can simultaneously analyze cations and anions in a single test. The analysis of acidic analytes in the negative-ion mode often does not offer extremely good sensitivity, but its ease of use has resulted in countless examples of negative mode analyses of anions in the literature. A sampling of such literature (which is most relevant to the later portions of this review) follows. Haloacetic acids (e.g., dichloroacetic acid and trichloroacetic acid) are frequently analyzed in environmental samples with negative-ion ESI (Kim et al., 2009b; Roehl et al., 2002; Barron & Paull, 2006). Perfluorocarboxylates have also been analyzed with negative-ion ESI. Perchlorate in food, beverages, biological systems, and environmental samples has been extensively studied with negative-ion mode ESI (Kirk et al., 2003; Backus et al., 2005; Aribi et al., 2006). Ochsenbein et al. used negative-ion mode ESI to determine explosives in lake water and tributaries (Ochsenbein, Zeh, & Berset, 2008). Phenolic compounds have been monitored in red wines with the negativeion mode (Biasoto et al., 2010). It should be noted that some neutral compounds can be detected in the negative-ion mode if they form halide or carboxylate adducts. This adduct formation is discussed in a recent review by (Gao, Zhang, & Karnes, 2005). However, small inorganic anions, such as chloride, bromide, and sulfate, are not easily detected in the negative-ion mode due to their low mass-to-charge ratio and/or poor ionization efficiencies. However, higher mass inorganic anions can be detected in the negative mode, such as oxyhalides and selenium and arsenic species (Cavalli, Polesello, & Valsecchi, 2005; Corr & Anacleto, 1996; Charles & Pepin, 1998; Afton et al., 2008; Charles, Pepin, & Casetta, 1996). The need for improved sensitivity for anionic analytes detected in the negative-ion mode has been a subject of research for more than a decade. Henriksen et al. monitored ion response for a series of acidic molecules in different spray solvents and found that acetonitrile improves sensitivity compared to methanol Mass Spectrometry Reviews DOI 10.1002/mas

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FIGURE 1. Sketch of the two ESI modes (positive and negative) to show the opposite direction of electron flow.

(Henriksen et al., 2005). When aqueous-organic mixtures were used as spray solvent, the intensity of anion signals decreased. Also, it was shown that analyte acidity does not dictate its ionization efficiency in the negative-ion mode. In addition, the phenomenon known as “wrong-way-round” ionization has been demonstrated a number of times (Mansoori, Volmer, & Boyd, 1997; Wu et al., 2004; Hua & Jenke, 2012). This technique describes unexpected ion responses for acidic analytes when acid is added to the spray solution. This counter intuitive effect on sensitivity is not totally understood, but it does offer a means to change ionization efficiency of certain acidic analytes. Finally, detection limits for anions detected in the negativeion mode have been improved via a variety of ion-pairing experiments. First, low concentrations of trialkylamines added to mobile phases enhance ionization efficiency of some anions (Ballantine, Games, & Slater 1997a; Storm, Reemtsma, & Jekel, 1999; Ballantine, Games, & Slater 1997b; Ballantine, Slater & Games 1995; Quintana & Reemtsma, 2004). The reason for this enhancement is not known, but it was postulated that alkylammonium cations can displace sodium counter-ions of acids in the spray solution. The alkylammonium-acidic analyte complexes are easily disassociated during electrospray and result in increased ion transmission for the anion of interest. Magnuson et al. reported enhanced sensitivity for perchlorate detection in the negative-ion mode after adding an alkylammoMass Spectrometry Reviews DOI 10.1002/mas

nium (decyltrimethylammonium bromide) surfactant to the spray solution (Magnuson, Urbansky, & Kelty, 2000a; Magnuson, Urbansky, & Kelty, 2000b). Perchlorate was detected as a perchlorate decyltrimethylammonium bromide ternary complex in the negative-ion mode. This ion-pairing technique followed, by monitoring of complex/adducts, directly foreshadows the PIESI method discussed here.

C. Negative-versus Positive-ion Mode The required potential for electrospray formation is expressed by the Smith equation (Smith, 1986): V ES

s ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi      pffiffiffiffiffiffi dgcosu 8x 8x ln ¼ 1:8  105 dg ln ¼ 4εo d d

ð1Þ

with : VES, the minimum required potential in volts for electrospray formation, d, the electrospray needle or capillary diameter in m, g, the solvent surface tension in N/m, u, the half angle of the Taylor cone in angular degrees, eo, the vacuum permittivity (8.8  10
12 J
1C2), x, the distance between the capillary tip and the counter electrode in m, 205

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The potential VES is the same in positive- or negative-ion mode. Table 1 lists VES values for different pure solvents and different apparatus configurations. It shows that water will need a higher voltage for electrospray formation than any other solvent. The capillary bore size is the other important parameter; smaller-bore capillaries will form the electrospray Taylor cone with a lower voltage than larger-bore capillaries. However, eluent flow rate and capillary bore are quadratically related so that smaller capillaries might work at such low flow rates that not enough ions can be collected. Note, this is true as long as the bore diameter is uniform. In nanospray, for instance, the bore size decreases toward the tip. A high voltage can cause electrical discharges, particularly in the negative ion mode. Figure 1 illustrates the electrical connections of the negative and positive ion modes. In negativeion mode, the capillary is negative and the electron circulation goes from the capillary tip to the counter-electrode plate. Stray electrons can easily initiate an electric discharge in this electronrich environment to create a noisy MS signal (Kebarle & Verkerk, 2009). Furthermore, solvent selection is critical when operating in the negative mode, where it was demonstrated that long chain alcohols, halogenated solvents, or SF6 addition can act as electron scavengers to reduce arcing and background noise (Cech & Enke, 2001). Unfortunately, these solvents are viscous and/or not appropriate in LC separations. Electrical arcing is much less likely in positive-ion mode, where higher potentials are possible with common protic solvents like methanol and water while maintaining a stable electrospray with low background noise.

V. PAIRED-ION ELECTROSPRAY IONIZATION (PIESI) According to the 2013 IUPAC definition, an adduct ion is “an ion formed by the interaction of a precursor ion with one or more atoms or molecules to form an ion containing all the constituent atoms of the precursor ion as well as the additional atoms from the associated atoms or molecules.” (Murray et al., 2013). The ESI process produces an abundance of adducts in the positive-ion mode. Proton- and sodium-adducts are easily formed. Early on, adduct formation was used to improve detection sensitivity by adding salts into the mobile phase (Gao, Zhang, & Karnes, 2005). Adduct formation is at the heart of the PIESI-MS technique because it capitalizes on sensitivity enhancement gained through complexation. PIESI-MS involves introduction of very low concentrations of structurally optimized ion-pairing reagents (IPRs) into the sample stream that

TABLE 1. Minimum voltage for electrospray formation. Solvent Methanol Ethanol Isopropanol Acetonitrile Water

D = 100 µm Capillary

Surface tension N/m

x = 1 cm

2 cm

4 cm

22.6 22.1 23 30 72.8

1800 1800 1800 2100 3200

2000 2000 2000 2300 3600

2200 2200 2200 2500 3900

x = 4 cm 6 cm

d = 50 µm

d = 150 µm

2300 2300 2300 2600 4100

1700 1700 1700 1900 3000

2500 2500 2600 2900 4600

VES voltage calculated with equation 1 for pure solvents (rounded to the nearest 100). A stable electrospray will typically require slightly more voltage than the listed minimum values.

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enters the ESI probe. Cationic complexes that form by analyte anions that adduct the IPRs are measured in the positive-ion mode at a higher m/z ratio with LODs several orders of magnitude better than what could be obtained with the same free anion at a much lower m/z and in the negative-ion mode (Soukup-Hein et al., 2007). Figure 2 shows a typical instrumental configuration to perform PIESIMS analyses. Typically, two pumps are used. One pump is used for sample introduction and chromatographic separation, and the other pump supplies a continuous flow of IPR solution. Both pumps’ effluent flow is mixed prior to entering the ESI probe. In some cases, mixing the IPR precolumn (i.e., placing the y-shaped mixing tee between the injector and the column; Fig. 2) can also allow for the utilization of the IPR for ion-pairing chromatography. Once the IPR/anion complex is formed, it is introduced into the mass spectrometer in the positive-ion mode. Either selected-ion monitoring (SIM) or selected reaction monitoring (SRM) can determine the anion of interest.

A. Development of the PIESI Technique

1. Dicationic IPRs Kirk et al. were the first to report the use of dicationic IPRs to form positive-ion pairs with the singly charged perchlorate anion (Kirk et al., 2005a). The following reaction describes the adduct formation process: D2þ þ A
! DAþ

ð2Þ

D2þ is the dicationic reagent that forms the DAþ adduct with A
, the anion of interest. After Kirk’s research, Martinelango et al. improved the sensitivity and selectivity of ion-pairing with perchlorate with specially synthesized IPRs (Martinelango et al., 2005). The high accuracy and sensitivity to detect perchlorate led to an unprecedented understanding of perchlorate amounts in dairy and breast milk. As a side note, an interesting editoral exchange (Braverman & Pearce, 2005; Kirk et al., 2005; Lamm et al., 2005a; Kirk et al., 2005c) debated these results. Ultimately, a special Analytica Chimica Acta issue (567) was dedicated to perchlorate determination with three separate papers that employ IPRs. In 2007, Martinelango et al. (Martinelango & Dasgupta, 2007) showed an IPR/perchlorate complexation example using a simple dication. Soukup-Hein et al. extended the dicationic PIESI approach to 34 singly charged anions (detected with a single dicationic IPR) to prove its general application and sensitivity (SoukupHein et al., 2007). It was observed that sensitivity of dicationic PIESI loosely followed the Hofmeister series, and that chaotropic anions were detected with the best LODs. For example, the LOD for the very chaotropic perfluorooctanoate anion was 0.12 pg injected (with a 5 uL injection volume), which equals a concentration of 60 ng/L (60 ppt or 0.145 nM). The gains in sensitivity are clearly illustrated in Figure 3. Five anions were detected in the positive-ion SIM mode (Fig. 3A) with PIESI, as well as, at higher concentrations in the negative-ion mode (Fig. 3B), with no IPR. Signal-to-noise (S/N) ratios were greatly improved with PIESI. For example, 1.43 ng of thiocyanate was detected with PIESI with a S/N of 138, Mass Spectrometry Reviews DOI 10.1002/mas

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Aldrich/Fluka). LODs for singly charged anions with the optimized IPRs are listed in Table 3. Figure 4 shows the comparison of MS detection of benzenesulfonate with direct negative-ion mode at m/z 157, positive-ion mode of the complex at m/z 543.3 after pairing with the #4 dication, and MS/MS at m/z 227.3 by observing the fragment obtained after loss of the anion and benzyl imidazolium group (Remsburg et al., 2008).

2. Tricationic IPRs

FIGURE 2. The instrumental configuration of HPLC–PIESI-MS/MS. The IPR is continuously post-column infused and mixed with separated fractions in a Y-type mixing tee before ESI-MS. Reprinted with permission Xu et al., 2013; copyright 2013 Elsevier.

whereas it was undetectable in the negative-ion mode, even when 10 more sample was injected (Fig. 3). Lastly, SoukupHein et al. showed that SRM can be used to further improve the LOD for anions by at least another order of magnitude (SoukupHein et al., 2007). Remsburg et al. further improved the dicationic PIESI technique by evaluating 23 different dications for their PIESIMS effectiveness (Remsburg et al., 2008). Through empirical observation, it was determined that flexibility of the dicationic IPR was a necessary structural feature for improved sensitivity. Ultimately, four dications (shown in Table 2) were identified as most-effective, and are now commercially available (Sigma/

The success of the dicationic PIESI technique to detect singly charged anions led to an analogous approach to detect divalent anions. Tricationic species, T3þ, can form positively charged adducts, TAþ, with divalent anions, A2
, as shown by the reaction (3): T 3þ þ A2
! TAþ

ð3Þ

Soukup-Hein et al. first showed proof of this concept by evaluating 17 (structurally rigid) tricationic IPRs for their ability to pair with 11 diverse divalent anions (Soukup-Hein et al., 2008). Figure 5 illustrates the proof-of-principle for tricationic PIESI. When two divalent anions (hexachloroplatinate and o-benzenedisulfonate) were paired with tricationic IPRs and detected in the positive-ion mode, their S/Ns were approximately 5–20 greater than negative-ion mode detection, where 10 more analyte was injected. One tricationic IPR was most successful (#5 in Table 3). With this trication, several good LODs for divalent anions were reported, and summarized in Table 3.

FIGURE 3. A comparison of chromatographic separation and sensitivity of five anions on a Cyclobond I column detected in the (A) positive and (B) negative SIM modes. The mass injected in (B) is 10 that of (A) for SCN, TFO, and BZSN, 5 for PFOA, and the same for NTF2. The mass injected in (A) is: 1.43 ng SCN, 9.92 ng TFO, 1.16 ng BZSN, 0.68 ng NTF2, and 1.30 ng PFOA. The column was equilibrated for 15 min with 100% water with a linear gradient to 100% MeOH, begin at 3 min and complete at 9 min. Flow rate was 300 mL/min. In (A), the dicationic salt solution (40 mM in MeOH) was added post-column at 100 mL/min, whereas in (B) it is methanol only. SCN: thiocyanate; TFO: triflate; BZSN: benzenesulfonate; PFOA: perfluorooctanoic acid; NTF2: trifluoromethanesulfonimide. Reprinted with permission Suokup-Hein et al., 2007, copyright 2007 American Chemical Society.

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TABLE 2. Structures and properties of optimized PIESI-MS ion-pairing reagents.

The code number corresponds to the Sigma product. n.a., not commercially available.

Capitalizing on earlier reports of the advantages of IPR structural flexibility, Breitbach et al. produced a series of linear flexible tricationic IPRs (Breitbach et al., 2008). This study included 16 novel flexible trications and two rigid trications (the most-successful one and a moderately successful one as reported by Soukup-Hein) for comparison. Linear flexible tricationic IPRs produced better LODs for divalent anions (Table 3). In fact, the LOD for sulfate was improved 25 with the best flexible trication versus the best rigid trication. Also, the LOD for sodium nitroprusside (Fe(CN)5NO2
) was decreased to 7 pg (5 ul injection), corresponding to a concentration of 1.4 mg/L or 6.5 nM. This brightly red-colored salt seems easy to detect; however, a modern voltametric sensor had a LOD of only 100 nM (Pereira & Zanoni, 2007) or 15 times worse than the PIESI LOD reported by Breitbach et al. (Breitbach et al., 2008). Overall, two flexible trications (#6 and #7 in Table 2) were the most-successful tricationic IPRs. 208

Taking the most-successful (and commercially available) rigid and flexible trications, Warnke et al. extended tricationic PEISI towards a wide variety of divalent anions (Warnke et al., 2009b). LODs for the additional anions are reported in Table 3. Previously, sulfur-containing dianions were monitored with CE (indirect spectrophotometric detection) to the mM concentration levels; e.g., the LODs for SO42
, S2O32
, S2O82
, and S4O62
were respectively listed as 2.5 mM (0.24 mg/L), 3 mM (0.34 mg/L), 5 mM (1 mg/L), and 5 mM (1.1 mg/L) (Motellier & Descostes, 2001). The PIESI LODs for the same anions are listed in Table 3 as, 42 nM (4 mg/L), 0.11 mM (12 mg/L), 0.13 mM (25 mg/L), and 45 pM (10 ng/L), respectively. These LODs are 60-times, 30-times, 40-times, and 110,000-times lower, respectively (equals five orders of magnitude better LOD for the tetrathionate dianion, S4O62
). Tricationic PIESI LODs were improved with SRM. In SRM, the dianion-trication complex is trapped, excited, and the transition to a fragment is monitored at a lower m/z ratio Mass Spectrometry Reviews DOI 10.1002/mas

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TABLE 3. LODs for anions detected with PIESI SIM MS. Pairing cation

LOD (inj pg)

LOD (g/L)

Monovalent anions BrNO3NO3NO3NCOClO4IIBenzoate Benzenesulfonate Benzenesulfonate Chloroacetate Chloroacetate Perfluorooctanoate Perfluorooctanoate

1 3 2 4 2 1 3 2 1 3 1 2 4 1 3

60 1.1 2 .0 4 .0 60 10 1.1 2.0 17 1.0 2.0 6.0 10 0.12 0.25

3.0 E-05 5.5 E-07 1.0 E-06 2.0 E-06 3.0 E-05 5.0 E-06 5.5 E-07 1.0 E-06 8.0 E-06 5.0 E-07 1.0 E-06 3.0 E-06 5.0 E-06 6.0 E-08 1.3 E-07

Breitbach, 2010 Remsburg, 2008 Remsburg, 2008 Remsburg, 2008 Remsburg, 2008 Soukup-Hein, 2007 Remsburg, 2008 Remsburg, 2008 Breitbach, 2010 Remsburg, 2008 Breitbach, 2010 Remsburg, 2008 Remsburg, 2008 Remsburg, 2008 Remsburg, 2008

Divalent anions SO42SO42S2O32S2O32S2O82S4O62AsO42CrO42Cr2O42Cr2O42Fe(CN)5NO2Fe(CN)5NO2MnO42MoO42PtCl62PtCl62ReCl62SeO42o-Benzenedisulfonate m-Benzenedisulfonate Bromosuccinate Dibromosuccinate Ethanedisulfonate Fluorophosphate Methanedisulfonate Oxalate Phenylphosphate

7 6 5 7 7 7 7 7 5 7 6 5 5 7 5 7 7 5 5 5 5 7 7 7 6 6 7

(inj pg) 20 4 50 125 62 120 0.5 750 250 1000 6200 7.0 7.5 375 150 75 40 15 75 15 8.8 75 120 35 26 30 12 40

(g/L) 4.0 E-06 9.0 E-05 2.4 E-05 1.2 E-05 2.5 E-05 1.0 E-08 1.5 E-04 5.0 E-05 1.9 E-04 1.2 E-03 1.4 E-06 1.5 E-06 7.5 E-05 3.0 E-05 1.5 E-05 8.0 E-06 3.0 E-06 1.5 E-05 3.0 E-06 1.8 E-06 1.5 E-05 2.4 E-05 6.1 E-06 5.2 E-06 6.0 E-06 2.4 E-06 8.0 E-06

Breitbach, 2008 Breitbach, 2008 Soukup-Hein, 2008 Breitbach, 2008 Warnke, 2009b Warnke, 2009b Warnke, 2009b Warnke, 2009b Soukup-Hein, 2008 Breitbach, 2008 Breitbach, 2008 Soukup-Hein, 2008 Warnke, 2009b Warnke, 2009b Soukup-Hein, 2008 Breitbach, 2008 Warnke, 2009b Soukup-Hein, 2008 Soukup-Hein, 2008 Warnke, 2009b Soukup-Hein, 2008 Breitbach, 2008 Warnke, 2009b Breitbach, 2008 Warnke, 2009b Breitbach, 2008 Warnke, 2009b

Anion

(Warnke et al., 2009b). Typically, one to two orders of magnitude gains in sensitivity can be obtained by comparing the direct selected ion monitoring PIESI LOD with the SRM LOD for the same ion-pair. For particular cases, a gain of several orders of magnitude was obtained. For example, the SIM LOD for the phenylphosphate ion paired with Trication #7 was 40 pg (8 mg/L) (Table 3). The corresponding SRM LOD for the same ion-pair was 5 fg (1 ng/L), which is 8000x lower (Warnke et al., 2009b).

3. Tetracationic IPRs Continuing with the same reasoning, tetracationic salts should make adducts with trivalent anions to produce positively charged heavier complexes detectable in the positive-ion mode. Eighteen tetracationic salts were synthesized and tested for PIESI with trivalent anions (Zhang et al., 2010). The two best Mass Spectrometry Reviews DOI 10.1002/mas

Ref.

tetracationic IPRs are listed in Table 2. Table 3 lists the LODs obtained with a selection of trivalent anions. Trivalent anions were mostly detected as þ1 ion-pairs at the m/z ratio that corresponded to the trivalent anion complexed with the tetracation. However, some trivalent anions were detected with several positive charges. For example, PO43
was detected as a þ 2 complex, with tetracationic pairing agent #8, at m/z 409.4 after adducting one proton. This adds to the versatility and sensitivity of tetracationic IPRs, because they can complex and detect not only trivalent anions, but also divalent and monovalent anions (Zhang et al., 2010).

B. PIESI Applications and Its Combination with Separation Systems Though a relatively new technique, PIESI-MS has proven useful in many applications where sensitive detection of anions with 209

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TABLE 3. (Continued) Pairing cation

LOD (in jpg)

LOD (g/L)

8 8 9 9 9 9 8 8 8

375 37 20000 30000 500 18 125 150 250

7.5 E-05 7.5 E-06 4 mg/L 6 mg/L 1.0 E-04 3.6 E-06 2.5 E-05 3.0 E-05 5.0 E-05

8

2500

5.0 E-04

Zhang, 2010

8 9

2500 175

5.0 E-04 3.5 E-05

Zhang, 2010 Zhang, 2010

9

100

2.0 E-05

Zhang, 2010

4 4 4 4 4 3 3

(in jpg) 400 250* 300* 300 500* 170* 750

(g/L) 8.0 E-05 5.0 E-05 6.0 E-05 6.0 E-05 1.0 E-04 3.5 E-05 1.5 E-04

Warnke, 2009a Warnke, 2009a Warnke, 2009a Warnke, 2009a Warnke, 2009a Warnke, 2009a Warnke, 2009a

9 9 9 9 9

(in jpg) 0.5 0.015 5 0.01 5

(g/L) 1.0 E-07 3.0 E-09 1.0 E-06 2.0 E-09 1.0 E-06

Dodbiba, 2011 Dodbiba, 2011 Dodbiba, 2011 Dodbiba, 2011 Dodbiba, 2011

8

0.005

1.0 E-09

Dodbiba, 2011

Metal chelates Cu2+[EDDS] Mg2+[EDDS] Ca2+[EDDS] Co2+[EDDS] Fe2+[EDDS] Fe3+[EDDS] Ni2+[EDTA] Mn2+[EDTA] Ag2+[EDTA] Ru2+[EDDS] Sn2+[EDDS]

9 9 9 9 9 9 9 9 8 9 9

(in jpg) 0.18 0.21 0.4 0.44 0.84 2.8 0.72 1.6 24 6.1 72

(g/L) 3.6 E-08 4.2 E-08 8.0 E-08 8.8 E-08 1.7 E-07 5.6 E-07 1.4 E-07 3.2 E-09 4.8 E-06 1.2 E-06 1.4 E-05

Dodbiba, 2012 Dodbiba, 2012 Dodbiba, 2012 Dodbiba, 2012 Dodbiba, 2012 Dodbiba, 2012 Dodbiba, 2012 Dodbiba, 2012 Dodbiba, 2012 Dodbiba, 2012 Dodbiba, 2012

Nucleotides cGMP cAMP cCMP

9 9 9

(in jpg) 30 30 30

(g/L) 6.0 E-06 6.0 E-06 6.0 E-06

Dodbiba, 2010 Dodbiba, 2010 Dodbiba, 2010

Anion Trivalent anions _ PO43 _ 3 P3O9 _ Co(NO_2)63 3 RhCl_6 VO43 _ Co(CN)63 _ N(CH2COO)3 Citrate Phosphoformate Oxalomalic tricarboxylate Indigo(trisulfonate) Tartrazine 8-metoxypyrene-1,3,6trisulfonate Bisphosphonates Alendronate Clodronate Etidronate Ibandronate Neridronate Risedronate Zoledronate Phospholipids Cardiolipin Phosphatidylcholine Phosphatidic acid Phosphatidylserine Phosphatidylinositol Sphingosyl phosphoethanolamine

MS is required. Dodbiba et al. applied PIESI to detect nucleotides, including cyclic nucleotides, nucleotide mono-, di, and tri-phosphates, and di- and tri-nucleotides (Dodbiba et al., 2010). The most-successful dicationic, tricationic, and tetracation IPRs were evaluated; tricationic and tetracationic IPRs outperformed dicationic IPRs (Table 3). With PIESI SIM, the LOD for thymidine diphosphate was 750 better than its LOD in its uncomplexed form (i.e., in the negative-ion mode). This LOD was further improved by two orders of magnitude with SRM. Later Dodbiba et al. set record LODs (Table 3) for another class of analytes, phospholipids (Dodbiba et al., 2011). Trace level phospholipid detection can be difficult due to their negative or zwitterionic charge state. Phosphatidylcholine or phosphatidylserine are zwitterions, and cardio-

210

Ref. Zhang, 2010 Zhang, 2010 Zhang, 2010 Zhang, 2010 Zhang, 2010 Zhang, 2010 Zhang, 2010 Zhang, 2010 Zhang, 2010

lipin or phosphatidic acid bear two negative charges. Pairing phosphatidylserine with a tetracationic reagent allowed for the detection of 10 fg of this zwitterionic phospholipid, whereas the negative-ion mode LOD (with no IPR) was 4 ng, which is six orders of magnitude less sensitive than the PIESI LOD. Other zwitterionic phospholipids (i.e., phosphatidylcholine) were undetected in the negative-ion mode without PIESI (Dodbiba et al., 2011). Recently, acidic pesticides were detected at trace levels (Table 3) in environmental samples with pairing anions with dicationic reagents (Xu & Armstrong, 2013). A mixture of pesticides separated on an Ascentis1 C18 column with a methanol-water 67–33% v/v mobile phase at 0.3 mL/min flow rate and post-column addition of 0.1 mL/ min of a 40 mM aqueous solution of the dicationic IPR #2 Mass Spectrometry Reviews DOI 10.1002/mas

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TABLE 3. (Continued) Anion cTMP AMP IMP UMP TMP GMP CMP AD P TDP CDP ATP CTP Pesticides 2,4-D MCPA 2,4,5-T 2,4-DB MCPB 2,4,5-TB Cloprop Dichlorprop Fenoprop Mecoprop Dicamba 2,3,6-TBA Clopyralid Quinclorac Quinmerac Flupropanate Dalapon

Pairing cation 9 9 9 4 4 9 4 6 9 9 8 8

LOD (in jpg) 35 75 190 200 1 00 2 50 140 1 00 0 1 00 0 2 50 0 5 00 0 6500

LOD (g/L) 7.0 E-06 1.5 E05 3.8 E-05 4.0 E-05 2.0 E-05 5.0 E-05 2.8 E-05 2.0 E-04 2.0 E-04 5.0 E-04 1.0 E-03 1.2 E-03

Dodbiba, 2010 Dodbiba, 2010 Dodbiba, 2010 Dodbiba, 2010 Dodbiba, 2010 Dodbiba, 2010 Dodbiba, 2010 Dodbiba, 2010 Dodbiba, 2010 Dodbiba, 2010 Dodbiba, 2010 Dodbiba, 2010

3 2 3 2 2 2 4 4 2 4 4 4 3 2 4 4 3

(in jpg) 10 3.6 16 37 30 32 7 10 20 2.8 6 17 4.5 6 3.5 3.1 5

(g/L) 2.0 E-06 7.2 E-07 3.2 E-06 7.4 E-06 6.0 E-06 6.4 E-06 1.4 E-06 2.0 E-06 4.0 E-06 5.6 E-07 1.2 E-06 3.4 E-06 9.0 E-07 1.2 E-06 7.0 E-07 6.2 E-07 1.0 E-06

Xu, 2013 Xu, 2013 Xu, 2013 Xu, 2013 Xu, 2013 Xu, 2013 Xu, 2013 Xu, 2013 Xu, 2013 Xu, 2013 Xu, 2013 Xu, 2013 Xu, 2013 Xu, 2013 Xu, 2013 Xu, 2013 Xu, 2013

Ref.

Listed LODs were obtained in the SIM positive-ion mode, except *, which were detected in SRM mode.

(Table 2). The listed LOD for Cloprop was 7 pg. The pesticide LODs reported were between 3 and 5 orders of magnitude better than previously reported LC-MS values (Xu & Armstrong, 2013). Two studies used PIESI for sensitive analysis of metal cations in positive-ion mode MS (Dodbiba et al., 2012 and Xu

FIGURE 4. Overlapping chromatograms of three injections of 0.2 ng of sodium benzenesulfonate in a methanol/water 50/50 v/v flow stream. Black line: negative SIM of m/z 157. Blue line: positive SIM of the #4 complex at m/z 543.3 after post-column addition of 40 mM #4 dication methanolic solution to the flow stream. Red line: single reaction monitoring of m/z 227.3. Reprinted with permission Remsburg et al., 2008; copyright 2008 Springer.

Mass Spectrometry Reviews DOI 10.1002/mas

et al., 2012). Cationic metals are rarely detected in ESI-MS due to their hydrated state, poor surface activity, and low m/z ratios. However, they are positively charged. Thus, to detect cationic metals with PIESI, common chelating agents (e.g., EDTA) are used to form negatively charged metal chelates. The negatively charged metal chelates are paired with an IPR in PIESI-MS, and the resulting ternary complex is detected with an exceptional sensitivity that rivals ICP-MS, while offering speciation information (Table 3). In 2011, Tak et al. applied PIESI-MS to detect alkylphosphates (Tak et al., 2011). The sensitive detection of alkylphosphates is important, because they are used to detect chemical warfare agents. Due to alkylphosphates divalent anionic nature, trication #6 (Table 2) was used. The method improved sensitivity for this class of analytes to the 100 pg level. Later, the method was improved to detect alkyl alkylphosphates (monovalent anions), which utilized dication #1 (Table 2) (Tak et al., 2012). Flanigan et al. used PIESI to determine of inorganic improvised explosive device (IED) signatures, such as nitrate, chlorate, and perchlorate (Flanigan et al., 2011). The PIESI IPR complexed anionic analytes in an ion plume created with laser electrospray mass spectrometry (LEMS) to directly analyze solid IED residues. This report also highlighted the ability for PIESI to simultaneously detect uncomplexed cations as well as complexed anions in the positive-ion mode. Recently, Guo et al. evaluated PIESI-MS for analysis of performance-enhancing drugs. Many performance enhancing drugs (e.g., steroids) are metabolized and excreted as anionic glucuronide and sulfate conjugates, and as such, they are 211

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FIGURE 5. Comparison of positive (I, II) and negative mode ESI detection (III, IV) for hexachloroplatinate (I, III) and o-benzenedisulfonate (II, IV). Tricationic IPR in water were introduced into the carrier flow after anion injection in positive-ion mode, whereas only water was used in negative-ion mode (III, IV). Reprinted with permission Soukup-Hein et al., 2008; copyright 2008 American Chemical Society.

frequently detected in the negative-ion mode. However, these anionic metabolites are often in low concentrations that require more sensitive detection methods. PIESI-MS detected 11 anionic metabolites and resulted in sensitivity improvements of up to 10,000 times compared to other LC/ MS methods (Guo et al., 2014). With PIESI-MS, the LOD for testosterone glucuronide was reported to be 6 pg. Finally, PIESI-MS was applied to a sample to detect androsterone sulfate to accurately determine 1.16 ug/mL in the urine of a healthy male. As was mentioned previously, PIESI can be combined with separation systems. Lin et al. first demonstrated CE-PIESI-MS with a dicationic IPR (Lin et al., 2009). In CE-PIESI, the IPR can be added directly to the anion sample vial, to the CE run buffer, or to the nebulization make-up solvent. On-column addition (i.e., in the run buffer) yielded the best separation and detection results. Gerardi et al. extended CE-PIESI to tricationic 212

IPRs to detect several common organic and inorganic anions (Gerardi et al., 2012). Lastly, it is possible to add a PIESI IPR to a reversed-phase LC mobile phase. This allows the IPR to not only aid in the detection of anions as they enter the mass spectrometer, but to also improve chromatographic separation of anions. Separation of the bisphosphonates neridronate, etidronate, and clodronate (Fig. 6) was performed in this manner (Warnke et al., 2009). Without IPR in the mobile phase, the bisphosphonates were not well-retained on the C18 column. LODs with PIESI and bisphosphonates are listed in Table 3.

C. PIESI Mechanism To begin to understand the PIESI mechanism, which results in such high sensitivity for anion detection, the binding constants between IPRs and anions have been determined and related to

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FIGURE 7. Surface tension measurements for titration of dication #1 (see Table 2) with benzenesulfonate. This plot represents surface tension versus benzenesulfonate (BZSN) concentration in neat water and a 0.1 M aq. solution of the dication. Reprinted with permission Breitbach et al., 2010; copyright 2010 American Chemical Society.

FIGURE 6. An extracted ion chromatogram to represent LC separation of neridronate, etidronate, and clodronate with the tricationic reagent #6 (in Table 2) as a mobile phase ion-pair additive. This separation was performed on a C18 stationary phase with a mobile phase of 80:20 water:MeOH with 40 uM IPR concentration. The flow rate was 0.3 mL/min
1 and methanol was added into the effluent at a flow rate of 0.2 mL/min
1. The three trication–bisphosphonate complex m/z values were monitored simultaneously in SIM mode. Reprinted with permission Warnke et al., 2009; copyright 2009 Elsevier.

PIESI-MS LODs (Breitbach et al., 2010). Dications and singly charged anions have binding constants (determined in liquid phase by NMR titration) that range from 53 to 160 M
1. The binding constant values did not correlate well with Table 3 LOD values. An ESI-MS method to estimate binding constants in the gas phase was developed for the same dications and anions. Several orders of magnitude larger binding constants, between 1100 and 1.1 106 M
1, were obtained; those constants also relate poorly to Table 3 LODs. The much larger binding constants obtained with ESI-MS were considered to be related to a large enhancement in binding when the ion-pairs are desolvated (Beitbach et al., 2010). It was determined that binding in solution is necessary for PIESI, but not sufficient to result in the exceptionally low LODs that have been reported. Breitbach et al. also established that IPR/anion complexes can change the surface tension of water (Beitbach et al., 2010). Figure 7 shows the change of the surface tension of water and a bulk solution of IPR when sodium benzenesulfonate (NaBZSN) was added. A slight and continuous decrease of surface tension was measured with NaBZSN addition to water. Thus, the benzenesulfonate is not very surface active (Armstrong, Lafranchise, & Young, 1982). When the same BZSN additions were made to a 0.1 M aqueous solution of the dication 1,9nonanediyl-bis(3-methylimidazolium) fluoride (#1 in Table 2), Mass Spectrometry Reviews DOI 10.1002/mas

the surface tension decreased rapidly (Fig. 7). The dication IPR/ BZSN complex is seen with surface-active properties that lower the surface tension of water by about 18 dynes/cm. This behavior was observed for several other cationic reagents and different anions, and the surface tension-lowering was related to the observed LODs (Breitbach et al., 2010). Because the anion/IPR complexes prefer gas/water interfaces (i.e., the complexes act as surfactants) the equilibrium partitioning model (EPM) can be considered (Sherman & Brodbelt, 2005). It should be noted that another similar model, referred to as modified aerosol redistribution (AIR), also describes the effect of surfactants on charged droplets (Kornahren et al.,1982; Rundlett & Armstrong, 1996). In the EPM model, the electrospray-formed droplet is considered as biphasic between the droplet surface and its interior. The surface phase contains the excess charge and is more hospitable to surfactants. The interior is polar making it the location of choice for small ions and polar molecules. There is a partitioning of the cationic reagent, anion, and complex between the two phases as represented by Figure 8 (Breitbach et al., 2010). As the complexes form and the droplets shrink, the ion-pairs have a large affinity for the droplet surface to enhance ionization efficiencies as they rapidly partition away from the center of the droplet. When the binding equilibrium in the center of the droplet is disrupted by the continuous partitioning of the complex to the surface, more complex is formed in the center of the droplet to maintain the equilibrium constant. This kinetic enhancement is the driving force for the remarkably low LODs observed for these systems. The surface active nature of the complex also explained the success of flexible pairing agents, because they are more likely to form surfactant-like complexes with anions to produce better LODs compared to more rigid IPRs (Breitbach et al., 2010). Considering the need for surface activity of IPR/anion complexes, Xu et al. recently synthesized and evaluated two rationally designed IPRs (Xu et al., 2014). These new dicationic IPRs were unsymmetrical and had their two cationic moieties relatively close to each other, with one long-chain alkyl (i.e., a tetradecyl group) substituent on only one side of the IPR (see Figure 9A). This structure created a surface-active IPR before 213

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complexing an anion, which is in contrast to the dications reported by Breitbach et al. (Breitbach et al., 2010). A representation of the surface-active nature of the surfactant-like IPRs can be seen in Figure 9B. What Xu et al. showed is that, with the surface-active dications, the unsymmetrical IPR/anion complex forms on the surface of the droplet more readily than the symmetrical IPR/anion complex which partitions to the droplet surface as was described above. Nonetheless, the more surface-active dications resulted in complexes with higher surface activity than the non-surface active dications to enhance sensitivity to anions. Lastly, Xu et al. pointed out that, as the concentration of the surface-active dications is increased, there becomes a point where the droplet surface is saturated, and micelles of IPR can form in the center of the droplet to actually decrease partitioning of the anion to the surface (Fig. 9C). Thus, with surface-active IPRs it is necessary to use low concentrations of the IPR and to ensure that the surface is not saturated.

VI. CONCLUSIONS FIGURE 8. Equilibrium partitioning model. The outer region of this model represents the exterior, hydrophobic portion of the droplet, whereas the inner portion represents the neutral, hydrophilic portion of the droplet. D2þ, A
, and DAþ stand for the free dication (also represented by þ ------- þ), free anion, and complex species, respectively. The surface-active DAþ accumulates in the droplet outer layer with constant exchanges with the inner neutral and hydrophilic center. Reprinted with permission Breitbach et al., 2010; copyright 2010 American Chemical Society.

There are numerous analytical methods to detect and to quantitate anions. Ion chromatography is a reliable and robust method for anion analysis down to the mg level. However, detecting substantially lower concentrations can be problematic, as for example for the determination of perchlorate in the environment. In these cases, MS is the solution. The rapid improvements and spreading of reliable and user-friendly mass spectrometers have almost turned these once expensive and delicate instruments into robust detectors for separation methods. LC-MS is today present in most analytical laboratories. The detection of anions with MS is greatly improved with pairedion electrospray ionization, PIESI. In PIESI-MS, adducts are

FIGURE 9. (A) Structural representation of a symmetrical, non-surface active dicationic IPR and its unsymmetrical, surface-active analog. (B–C) Schematic of the partitioning of an analyte anion between the surface of an aerosol droplet and the bulk interior. When the concentration of the surface-active IPR is low (“B” above), it resides mainly at the surface of the droplet as will any associated anions. When the concentration of surface of the dicationic surfactant is high (“C” above), monolayer can form and all additional surfactant resides in the interior bulk solution. Thus, the anionic analyte has increased partitions to the interior bulk solution. Reprinted with permission Xu et al., 2014, copyright 2014 American Chemical Society.

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intentionally formed in the electrospray to turn low m/z anions into higher m/z ion-pairs that can be detected in the positiveionization mode with remarkably better S/N ratios compared to the classical negative-ionization mode. To conclude this review, it is pointed out that addition of low concentrations of multicationic entities into the electrospray could raise concern on source pollution. After several years of PIESI use, it was found that infusion of very low concentrations of pairing reagents (2– 10 mM) did not pollute the ionization source at all; on the contrary, in certain occasions (phospholipids), it seemed to clean the source by removing hydrophobic anionic entities that tightly adhere to the LC-MS tubing and the source internal walls.

ABBREVIATIONS APCI APPI BZSN C18 CE CI DART DBDI DESI EDTA EI ELSD EPM ESI FAB FID GC HILIC HPLC IC ICP IMS IPR ISE IUPAC kV L LEMS LILBID LOD MALDI min mL MS m/z ng nM NMR PIESI pg ppb ppt RPLC SESI SF6 SIM

atmospheric pressure chemical ionization atmospheric pressure photo ionization benzensulfonate octadecyl capillary electrophoresis chemical ionization direct analysis in real time direct barrier desorptive ionization desorptive electrospray ionization ethylenediaminetetraacetic acid electron ionization evaporative light-scattering detector equilibrium partitioning model electrospray ionization fast atom bombardment flame ionization detector gas chromatography hydrophilic interaction liquid chromatography high performance liquid chromatography ion chromatography inductively coupled plasma ion-mobility spectrometry ion-pairing reagent ion-selective electrode International Union of Pure and Applied Chemistry kilovolt liter laser electrospray mass spectrometry laser-induced liquid beam ionization/desorption limit of detection matrix-assisted laser desorption/ionzation minute milliliter mass spectrometry mass-to-charge nanogram nanomolar nuclear magnetic resonance paired-ion electrospray ionization picogram parts-per-billion parts-per-trillion reversed-phase liquid chromatography secondary electrospray ionization sulfur hexafluoride selected ion monitoring

Mass Spectrometry Reviews DOI 10.1002/mas

S/N SRM TLC TOF mg mL UV

&

signal-to-noise selected reaction monitoring thin layer chromatography time-of-flight microgram microliter ultra-violet

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