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Role of Electrochemistry in Desorption Ionization Mass Spectrometry (LS DESI MS) of Aqueous Samples Containing Electrolyte Salts. Wen Donq Looi, Laura Chamand, Blake Brown, and Anna F. Brajter-Toth Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.6b02406 • Publication Date (Web): 20 Oct 2016 Downloaded from http://pubs.acs.org on October 20, 2016

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Analytical Chemistry

Role of Electrochemistry in Desorption Ionization Mass Spectrometry (LS DESI MS) of Aqueous Samples Containing Electrolyte Salts. Wen Donq Looi,† Laura Chamand,‡ Blake Brown,† and Anna Brajter-Toth*† † ‡

Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, FL 32611-7200, USA Faculty of Chemistry, University of Strasbourg, 1 Rue Blasie Pascal, 67008 Strasbourg, France

ABSTRACT: The ionization of liquid samples in desorption ionization mass spectrometry (LS DESI MS), supplied continuously through a liquid interface separated in space from the spray emitter, was investigated in this work. The role of electrochemistry (EC) in the ionization process was addressed. The visual (observation) of the operation of the LS DESI MS system showed a thick spray plume generated by electrosonic ionization (ESSI) forming a liquid cone at the liquid interface. When the liquid interface was grounded the cone collapsed and the MS ion signal was lost, indicating that the LS was carried to the MS inlet by the spray that emerged from the cone. Ion signals in a new in-line and in angled LS DESI MS system, in electrospray ionization (ESI) MS, which produced the most intense ion signals when methanol/water solutions, and in electrosonic ionization (ESSI) MS of dopamine (DA), tyrosine (Tyr) and N,N-dimethyl-pphenylenediamine (DMPA) were evaluated in methanol/water and aqueous (aq) solutions. The effect on ion signal of geometric parameters and LS and spray solution flow rates was tested in in-line LS DESI MS. Of the methods tested, the analysis of aq LS containing electrolytes was simplest by LS DESI MS. The signal intensity was higher in in-line than in angled LS DESI MS. In online electrochemistry (EC)/LS DESI MS when 0 V was applied to EC cell Tyr ion signal was detected only at low pH (2.4).

New analytical methods have been central to the progress in life science research due in a large part to the developments in mass spectrometry (MS) especially in electrospray ionization (ESI) MS instrumentation and methods. Of special interest are the new contributions of MS, alone and in the combination with electrochemistry (EC), in EC/ESI MS, to the investigations of biological reactions by MS online, in close to real time, including the reactions responsible for oxidative stress.1,2 In all the applications, the efficiency of sample ionization processes determines the success of the MS analysis. ESI generates protonated (solvated) ions for MS detection when a high voltage (HV) is applied to the electrospray (ES) emitter capillary. ESI in the positive ion mode generates the protonated sample ions efficiently from methanol (MeOH)/H2O solutions containing small amounts of electrolytes such as acetic acid. However, the catch 22 is that the high positive voltage required for the ionization in the positive ion mode additionally leads to the oxidation of the sample components. Consequently, the protonated analyte is detected together with its protonated oxidation products (OPs), which complicate analysis. The development of new strategies for minimizing the changes in sample composition during the ionization processes is an ongoing effort. In addition,

electrochemistry of the ionization process has been exploited in different applications. Desorption ionization (DESI) mass spectrometry (MS) has been developed recently for the ambient analysis of solids3 and liquids.4 In liquid sample (LS) DESI MS, a LS capillary is placed some distance away from the spray emitter and delivers the LS continuously, while acting as the liquid ionization interface.4 Since the liquid and the emitter interfaces are separated in space, the positive HV is applied to the spray emitter that is not a part of the liquid interface. This design allows more flexibility in analysis, allowing different solutions to be supplied through the two interfaces. This has particular advantages in the online investigations of chemical reactions, as demonstrated recently. 4-12 Additonally, the ease of adoption of the ESI MS apparatus to DESI MS, the sensitivity, and the similarity of DESI and ESI mass spectra, and the limited sample preparation, has been exploited in analysis, in proteomics and forensics.5,13-18 The experimental parameters that control sensitivity in DESI MS include the ionization voltage, and the distance and orientation of the spray emitter, the sample stage, and the MS inlet.19 The original “angular” instrumental design of the liquid interface in LS DESI MS systems was based on the design of the sample stage (interface) that was developed for the

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Hamilton, Reno, NV, USA) is connected to a syringe pump (MDL 74900, Cole Parmer, Vernon Hills, IL, USA) and supplied the LS to the EC cell, through a silica capillary (20 cm, 360 µm OD, 180 µm ID). In LS DESI MS, the EC cell was not connected to the potentiostat. At flow rate of 200 µL/hr, the LS was transferred to the liquid interface from EC cell in ca. 1 min. The ESSI emitter (Fig. 1) comprised an outer silica capillary (5- 8 cm, 360 µm OD, 250 µm ID) for delivery (at 100 psi) of the N2 gas and an inner capillary (tapered, 200 µm OD, 100 µm ID), which extended ca. 0.5 mm beyond the outer capillary and delivered the spray solution. The outer capillary was sheathed with PEEK tubing (Idex Health & Sciences, Oak Harbor, WA) for rigidity. The same configuration of the capillary emitter was used in in LS DESI, ESSI and, without N2 gas flow, in ESI MS. The ESI solution at flow rate of 100 uL/hr was used as the spray solution in ESI and ESSI MS. Silica capillary (1.5 cm, 360 µm OD, 180 µm ID) acted as a liquid interface that continuously delivered the LS in in-line LS DESI MS (Fig. 1). A polished PEEK capillary (1.5 cm, 1588 µm OD, 127 µm ID; Idex Health & Sciences, Oak Harbor, WA) was used in angled LS DESI MS.22 Unless stated otherwise, in LS DESI MS the spray and the sample solution flow rate was 200 uL/hr. High voltage (HV) was 2.5 - 3.5 kV in ESI MS and 3 - 4 kV in ESSI and LS DESI MS. Mass spectrometry. The modified Bruker Daltonics (Billerica, MA) model APEX 4.7 T FTICR MS system was used,12 with ion source and ICR cell pressures at 6.0 to 7.0 × 10−6, and 1.0 to 2.0 × 10−10 torr, respectively. Fifty mass spectra scans were averaged. MS inlet capillary voltage was ca. 58 V during tuning of the MS system, with skimmer voltage at 18 V. Capillary voltage was adjusted2 between 55 - 69 V in 2 V increments with skimmer voltage at 18 V. A stable signal was recorded after 30 sec. Inlet MS capillary was maintained at 150°C. Geometry and flow rate. Distance and geometry adjustments at the LS interface were made first. DA (1 mM) ion signals of ([DA+H]+ m/z 154 and [(DA-NH3)+H]+ m/z 137) in ESI and AC buffer solutions (Table 1) were recorded twice times after each change of flow rate, in 1 min intervals, for a total of 3 min. Flow rate of the spray solution (or the LS) was changed, while the other flow rate was fixed at 200 µL/hr. In additional experiments, the same flow rate was maintained for the sample and the spray solution and each time both flow rates were changed. Flow rates were changed in random order. Liquid interface imaging during LS DESI MS. The LS DESI interface was illuminated with 532 nm 5 mW laser pointer (Laserpointerpro.com, Hong Kong) and was monitored using a microscope eye piece (10 times magnification). Videos were recorded with cell phone camera (HTC One, Taipei, Taiwan) while DA (1 mM; ESI solution) ion signal was continuously monitored by FT ICR MS. Liquid interface was grounded by connecting the EC cell with a wire to a metallic table, which supported the LS DESI stage and DA ion signal was monitored for 5 s before the wire was disconnected. DA ion signal was also recorded after the EC cell was connected to the potentiostat; the HV was connected last. Electrochemistry online (EC/LS DESI MS). The twoelectrode flow-through EC cell (3.15 x 10-3 cm3) that was used in EC/LS DESI MS (Fig. 1) contained a 50 µm PTFE gasket,

analysis of solid samples by DESI MS, and on the understanding of the ionization process in DESI based on the “droplet pickup” ionization mechanism of solids. 4,5,20,21 According to this mechanism, the analyte is desorbed from the sample stage and is transported to the MS inlet by a secondary spray (“droplet pickup”), generated after HV is applied to the electrosonic ionization (ESSI) spray emitter, away from the liquid interface. In this model, the analyte is ionized as in ESI MS.5,20,21 An alternative mechanism proposed for the ionization of solids in DESI, involves a chemical ionization step before the analyte is desorbed into the secondary spray.5,13 New insights into the LS desorption ionization process were obtained in this work, using a new design of the LS DESI MS system. Different sample and spray solution compositions, were tested under varying experimental conditions, using the in-line12 and the traditional “angular” LS DESI MS system,4,22 as well as the ESSI and ESI MS. In addition to the new ionization model for LS by DESI, the results provide new information about the role of electrochemistry in the ionization processes of structurally different analytes. Analysis of aq samples containing electrolyte salts using in-line LS DESI MS, including by electrochemistry (EC) online in EC/LS DESI MS is greatly simplified and is the main advantage of this technique over ESI MS.12

EXPERIMENTAL SECTION Materials. All chemicals were used as received. Methanol (MeOH) (99.9%), ammonium acetate (98%), formic acid aq (HFA) (≥88% w/v), sodium phosphate monobasic monohydrate (>99%), and anhydrous sodium phosphate dibasic (>99%) were from Fisher Scientific (Fair Lawn, NJ). Glacial acetic acid (HAc) was from B&A Allied Chemical Company (Morristown, NJ). 2-(3,4-Dihydroxyphenyl)ethylamine (dopamine, DA) hydrochloride (98%), L-2-amino3-(4-hydroxyphenyl) propanoic acid (L-tyrosine, Tyr) (≥98%), and ammonium formate (>99%) were from Sigma Chemical Co. (St. Louis, MO). All solutions were prepared in doubly deionized water. Phosphate buffer (PBS) pH was adjusted with 0.1 M NaOH. Table 1. Composition, conductivity, and pH of sample and spray solutions. Solution

Composition

pH

Phosphate buffer (PBS) AC buffer

20 mM NaH2PO4, 11 mM Na2HPO4 0.1 M HAc, 0.1 M NH4Ac 50/49/1 vol% MeOH/H2O/HAc (0.174 M) 0.1 M HFA, 0.1 M NH4FA 1% HAc (0.174 M)

7.4

Conductivity (µS/cm) 3020

4.8

4120

4.3

120

3.8

4090

3.0

620

1% HFA (0.236 M)

2.4

2920

ESI solution

FA buffer HAc aqA B

HFA aq A

23 B

pKa 4.76 ; pKa 3.75

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LS and ESSI interface design. In-line LS DESI MS system (Fig. 1) has been described.12 LS capillary was connected to the EC cell through a ferrule. A syringe (250 µL, 1700 series,

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which separated stainless steel (SS) 0.63 cm2 WE and CEs.12 A potentiostat equipped with a model 179 digital coulometer (Princeton Applied Research 173, Oak Ridge, TN, USA) controlled cell voltage (Fig. 1). Electrochemistry off line. The BAS-100 electrochemical analyzer (Bioanalytical Systems, West Lafayette, IN, USA)

with a three-electrode EC cell with a pyrolytic graphite working electrode (PGE) (ca. 9 mm2), SCE, and Pt counter electrodes was used in cyclic voltammetry (CV) experiments. The PGE was polished on 600-grit SiC paper (Mark V Laboraratory, Granby, CT, USA) that was lubricated with doubly deionized water using a polishing wheel (Ecomet I,

Figure. 1 (A) LS DESI MS system with electrosonic spray ionization (ESSI) emitter. EC cell is connected to a potentiostat in EC/LS DESI MS but not in LS DESI MS; (B) thin layer EC cell design.

Buehler Ltd., Evanston, IL, USA). The polished electrodes were sonicated for 5 min in 50/50 H2O/EtOH and the polishing/cleaning procedure was repeated after three CV scans. CV scan rate was 200 mV/s.

(crowns) in the craters. The random splashing of the liquid is also expected when the thickness of the liquid film impacted by the spray < the droplet dia, when the We does not apply.24,25 The We and the number of droplets that are cast off increases as the size of the craters increases. When the We ≈ 180, the craters expand into hemispheres and the droplets are cast off in a relatively orderly fashion. In 50/50 vol% MeOH/H2O ESSI-generated spray (100 µm ID, 200 µm OD, HV 5kV, N2 150 psi), the predicted velocity of spray droplets is high, ca. 120 m/s on average, with the average droplet dia of 3.7 µm.21 When this spray impacts a MeOH/H2O film, the predicted We = 1450; the We = 670 when the film is aq, and is 760 when both liquids are water. Fewer droplets are thus expected from aq films, since the We is lower for those films. However, similar sensitivity has been reported when MeOH/H2O spray was used in in-line LS DESI MS in the analysis of aq and MeOH/H2O liquid sample films.12 Clearly, liquid-liquid interactions are not the only factor that impacts sensitivity in LS DESI MS. Of relevance is also the cross section of the spray at the point of impact with the LS film. The spray cross section increases as the distance between the point of contact and the

RESULTS AND DISCUSSION Liquid-liquid interactions in LS DESI MS. The liquid spray-liquid sample interactions when the LS film thickness> the spray droplet dia, can be characterized using the Weber number (We) (eq. 1) 24,25:

(1) where v is the average velocity of the spray droplet (m/s); l droplet length (or more typically dia, m); ρ density of the spray solution (kg/m3), which is 915 kg/m3 (20°C) for 50/50 vol% MeOH/H2O; 26 σ surface tension of the impacted liquid (N/m); 0.073 N/m (20°C) for water 27; 0.034 N/m (20°C) for 50/50 vol% MeOH/H2O.27 When the We ≈ 60 and the LS film thickness> the dia of the spray droplet, the film liquid impacted by the spray splashes randomly, and craters form in the film while the liquids mix and coalesce.25 Droplets are cast off from the thin tops

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that were eroded in the sample surface by the spray.5,20 In this work, the sensitivity was higher in-line LS DESI MS (Table 2) where the contact area with the liquid sample capillary impacted by the spray was larger than in angled LS DESI MS. In angled LS DESI MS, the impacted area was at the top of the LS

emitter increases, and is determined by the design and operation of the LS DESI MS system, and solution composition. In solid sample DESI MS, the reported cross section of MeOH/H2O ESSI-generated spray (flow rate 6 µL/hr, ID 2 mm, intensity decreased as the cone collapsed. For y1, deviations of < 0.5 mm led to ion signal loss and with changes in y1, the cone shifted.

Figure 4. MS inlet-liquid interface- ESSI spray interface in inline DESI. (B) and (C) - top view. (D) and (E) - side view.

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(B)-(E) spray image based on visual observation of liquid interface. See text for details. Optimization of distance z1 (Fig. 4D) is illustrated in Fig. 5. For z1 > 2.5 mm, the secondary spray was difficult to maintain since droplets (rather than a cone) formed at the capillary. When z1 < -0.5 mm (Fig. 4E), the spray bypassed the liquid interface and the ion signal was not detected.

it simplifies electrochemical investigations online and improves reaction efficiency by improving conductivity of the LS.12,32 This was demonstrated in analysis of Tyr and, previously, in analysis of DMPA.12 The results verify that sensitivity is generally higher in-line than in angular LS DESI MS. In both systems observations of the liquid interface showed a thick droplet plume, forming a “liquid bridge” between ESSI emitter and the LS capillary. The “bridge” is a direct illustration of the electric field between the interfaces that results in “electrochemistry” at the LS interface in DESI. As a result of the electric the liquid cone forms at the LS capillary edge of the liquid interface and generates a secondary spray that is smaller than the thick spray form the ESSI. The small secondary spray that emerges from the liquid cone is able to carry the LS to the MS inlet as a result of the electric field between the liquid interface and the MS inlet. Ion signal intensities were lower in LS DESI than in ESI MS since the electric field required for the ionizations is weaker at the liquid interface in LS DESI MS than the electric field at the ES emitter in ESI MS. In LS DESI MS intensities of ion signals generated from LS in ESI solution were higher than from aq solutions since methanol (MeOH; present in ESI solution at ca. vol 50%) facilitates sample ionization from the spray droplets because of its volatility, which reduces droplet size, increasing charge density at the droplets. However, in LS DESI MS of aq LS, the sensitivity and stability of the ion signal were still quite good, aided by the ESI spray solution mixing with the LS at the liquid interface. The aq LS generated signal much more stable signals in LS DESI MS than in ESI or ESSI MS. which were stable in the presence of electrolyte salts in the LS. Good sensitivity in LS DESI MS in the presence of high electrolyte concentration in the LS compared to the analyte concentrations, was observed in spite of the predictions of the suppressing effect of high electrolyte concentration on analyte ion signal intensity.68 Eq. 2 has been used to describe the relationship between the intensity of the analyte ion signal (IA,ms) and the electrolyte [E+] and the analyte [A+] concentrations in ESI MS:

Figure 5. DA base peak intensity in in-line LS DESI MS with distance z1 (Fig. 4). DA (1mM) in ESI solution. Spray and LS solution flow rate 200 µL/hr. LS and spray solution flow rate. Effect of flow rate on signal intensity in LS DESI MS, has not been reported. Different flow rates have been used in previous work.1,5,64,65 The effect of solution and LS flow rate on the average ion signal intensity in-line LS DESI MS is illustrated in Fig. 6A. At the flow rate of 100 µL/hr the signal was high but the secondary spray was difficult to maintain and the ion signal strongly fluctuated. Fig. 6B illustrates changes in signal intensity with flow rate, when one flow rate was constant at 200 µL/hr. With the increasing flow rate of either solution, the LS ionization efficiency decreased. A similar decrease in ion signal intensity at in ESI MS1 at high flow rates has been attributed to increase in droplet size in the spray.29 In LS DESI, oversupply of LS with the increasing flow rate can impair generation of the secondary spray thus limiting the ion signal.

IA,ms p = ,

(2)68

where p is instrumental detection efficiency, iES is electrospray (ES) current (A), IA,g is analyte ion current (A), f is the fraction of droplets converted into gas phase ions, and kA and kE are the conversion rate constants for analyte and electrolyte from solution into gas phase ions. Eq. 2 predicts suppression of ion signal (current) IA,g at high electrolyte concentrations [E+]. 69 However, when [E+] >>[A+], eq. 2 reduces to : , (3)

Figure 6. DA base peak intensity with flow rate in in-line LS DESI MS. (A) ESSI spray solution flow rate; LS flow rate 200 µL/hr; (B) LS flow rate; ESSI spray solution flow rate 200 uL/hr. (C) Spray solution and LS flow rates changed simultaneously. DA (1 mM) in ESI solution (B) and AC buffer (A, C). ESI spray solution. In agreement with the results discussed in the text DA ion signal intensity is higher from ESI than aq solutions.

where iES = iE. This means that when [E+] >>[A+], ES current iA,g is inversely dependent on only the electrolyte concentration [E+].68 But, since ES current iE ∝ [E+]3/7,68 the substitution into eq. 3 shows that, under these conditions, the analyte ion signal IA,g, ∝ [A+]/[E+]4/7 with lesser dependence on the electrolyte concentration, decreasing with [E+]4/7 not [E] as predicted by eq. 3. Assuming other parameters are constant, this means that at high electrolyte concentrations the suppressing effect of electrolyte is less than when

CONCLUSIONS The main advantage of in-line LS DESI MS (over ESI and ESSI MS) is in the analysis of aq samples containing electrolyte salts.4,12 Typically, MS analysis of aq samples is problematic and in presence of electrolyte salts which causes rapid contamination and ultimately shuts down the MS system.66,67 Improved tolerance of LS DESI MS to the presence of salts in the sample allows sustained analysis without significant contamination or clogging observed in ESI MS. This is significant in different areas; in EC/LS DESI MS

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concentrations of electrolyte and analyte are similar (eq. 2), and both are high.68,69 This means that as long as the MS ion signal is maintained without a significant contamination of the MS system, the suppressing effect of electrolytes could be lower at electrolyte concentrations >> than analyte concentration. LS DESI MS analysis of aqueous samples in the presence of salts is likely successful in part due to this effect. It is also due to the fact that the spray solution combines with the aq LS solution before the secondary spray enters the MS inlet. However, as predicted by the eqts and demonstrated in this work ion signals are lower for aq LS with electrolytes. Nevertheless, LS DESI MS is a viable method for the analysis of at low analyte concentrations in LS aq containing salts. LS DESI MS is feasible because of electrochemistry, which establishes the electric field and is involved in charging of the liquid interface.

AUTHOR INFORMATION Corresponding Author *Email: [email protected]. Tel: 352-392-7972. Fax: 352-3924651.

Notes The authors declare no competing financial interest. Author Contributions The manuscript was written through contributions of all authors.

ACKNOWLEDGMENT The authors are grateful towards Professor John R. Eyler for access to his FT-ICR MS and his guidance on the instrument, and to Professor Nicolas C. Polfer for access to his lab’s resources.

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