Doped Argon Surface Desorption Dielectric-barrier Discharge

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Doped Argon Surface Desorption Dielectric-barrier Discharge Ionization Mass Spectrometry for Fragile Compounds Hong Zhang, Jing He, Li-Na Qiao, Kai Yu, Na Li, Hong You, and Jie Jiang Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.8b01304 • Publication Date (Web): 03 Jul 2018 Downloaded from http://pubs.acs.org on July 3, 2018

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Analytical Chemistry

Doped Argon Surface Desorption Dielectric-barrier Discharge Ionization Mass Spectrometry for Fragile Compounds Hong Zhang,b Jing He,a Lina Qiao,b Kai Yu,a Na Li,a Hong You,a,b and Jie Jianga* a

School of Marine Science and Technology, Harbin Institute of Technology at Weihai, Weihai, Shandong 264209, P. R. China b School of Municipal and Environmental Engineering and State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, Heilongjiang 150090, P. R. China Corresponding Author: [email protected] ABSTRACT: Argon-surface desorption dielectric-barrier discharge ionization (Ar-SDDBDI) in conjunction with dopants was reported for rapid and sensitive determining of fragile compounds. In dopant/Ar-SDDBDI, analytes are ionized primarily through proton transfer with dopant ions, which are formed in Ar plasma. Different from He, dopant/Ar-SDDBDI generates low energetic ions, and therefore fragmentation is suppressed. It thus significantly simplifies the mass spectra and the assignment of one peak. Dopants ranging from organic solvents to gaseous materials were systematically studied. The application of dopant/Ar-SDDBDI was demonstrated by analysis of multiple compounds, including antibiotics, amino acids, fatty acids, hormones, pharmaceuticals, and peptides. Rapid profiling of chemicals in such complex matrixes including mixtures and drug tablets was also tested. Positive and negative mass spectra with little to no fragmentation for compounds in the pure state and as mixtures were readily achieved. Limits of detection (S/N = 3) were determined to be 0.60 and 0.36 pmol, respectively, for the analysis of L-alanine and metronidazole. Furthermore, the demonstration applications also included imaging of an “H” character under ambient conditions. These results indicate that the technique by combining of Ar-SDDBDI with dopants exhibits high sensitivity, high spatial resolution and very low degree of fragmentation, which render it a potential tool for fragile compounds analysis in mass spectrometry imaging.

Rapid, accurate, and effective ionization method that can form intact analyte ions from sample surface without any pretreatment is of importance to medical and biological research.1,2 The spray-based methods, especially desorption electrospray ionization (DESI), have seen significant use in surface analysis.3-6 Alternatives to spray sources based on exposure of the sample to a plasma have certain advantages associated with low energy consumption, solvent-free method, and easy miniaturization. These methods have included direct analysis in real time (DART),7 dielectric-barrier discharge (DBD),8 low temperature plasma (LTP),9 plasma-assisted desorption ionization (PADI),10 nanotip ambient ionization mass spectrometry (NAIMS),11 liquid sampling-atmospheric pressure afterglow microplasma ionization (LS-APAG),12 and microwave-induced plasma desorption/ionization (MIPDI).13 Dielectric-barrier discharge (DBD) has emerged as a popular technique in surface analysis. The discharge is achieved by simply positioning one or more insulating layers in the current path. Up to date, it has been developed to different versions by adjusting and modifying the electrode configurations.14 Because the formed microplasma can directly interact with the sample surface, it allows rapid and convenient analysis of the objects with any shapes. With the appealing features of simplicity and its low memory effects and ion suppression, the DBD ion source is widespread in many applications, including explosives,15 food safety,16 perfluorinated compounds,17 pharmaceuticals,18 reaction monitoring,19 and even with imaging of paintings20 as well as biomolecules21. Furthermore, DBD with helium as discharge gas is regarded as a homogeneous dis-

charge mode and a soft ionization process, which mostly produces protonated or deprotonated species. However, fragmentation is observed in the case of some compounds analysis.8,9,22 Generally, the fragmentation complicates the mass spectra and influences determination of whether a particular peak is an independent species or merely a fragment in a mixture. Replacement of helium with argon has been approved to facilitate DBD-MS analysis by generating minor fragmentation, but this reduces absolute intensity on the analytes. Another approach is admixture of dopants into argon. It allows additional Penning ionization23,24 and thus improving detection sensitivity. Depending on argon rich in dopants, detection of a range of compounds has been done in different DBD types from conventional apparatus to other variants such as plasma jet.23 However, none of these studies concerns with compounds that are prone to fragment using He, and limited information on dopants is provided since only a few dopants have been investigated in the researches.23,24 Furthermore, MS has not been coupled with the method to locate the distribution of fragile compounds, a capability recently shown importance for biomedical research.3,5 Surface desorption dielectric-barrier discharge (SDDBDI)25 has advantages of high-efficiency ion transmission and high spatial resolution imaging. SDDBDI has shown to be effective in analysis of different compounds, including fatty acids, amino acids, and therapeutic drugs. Taking the advantage of highefficiency ion transmission, SDDBDI achieves high spatial resolution (22 µm) without significantly sacrificing the MS

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sensitivity. If such a method is capable of locating fragile compounds with intact molecules and high signal intensity, its value would be considerable. In the present study, argon SDDBDI (Ar-SDDBDI) in conjunction with dopants was demonstrated for the analysis of compounds that are prone to fragment in He-DBD. Different from He-DBD, dopant/Ar-SDDBDI generates low energetic ions, and therefore little to no fragmentations and comparable MS sensitivity are obtained. Together, these capabilities benefit for compounds fragmented using He as discharge gas. Dopants ranging from organic solvents to gaseous materials were systematically evaluated. A very low degree of fragmentation enabled the determination of a wide range of fragile compounds in the pure state and as mixtures in both positive and negative ion modes. Ar-SDDBDI rich in dopants for imaging of fragile compounds is also included. EXPERIMENTAL SECTION Materials Acetonitrile and methanol were purchased from SigmaAldrich (Darmstadt, Germany). Dichloromethane, acetone, toluene, fluorobenzene, ethanol, 2-propanol, and antibiotics were purchased from J&K Chemical CO. (Beijing, China). Amino acids, fatty acids, guaiacol, propazine, octopamine, 5hydroxytryptamine, normetanephrine, glucose, ferulic acid, capsaicin, peptides, and lipids were purchased from SigmaAldrich (St. Louis, MO, USA). Acetaminophen and ibuprofen tablets were purchased from Sansei Pharmaceutical (Harbin, China). Discharge gases (He, Ar) and gaseous dopants (NH3, H2S) of purity ≥ 99.99% were purchased from Jinghua Industry Co. (Hangzhou, China). The tungsten nanotips with size of 0.5 µm were purchased from GGB Industries, Inc. (Naples, FL, USA). Ultrapure water was obtained from a Milli-Q water purification system (Milford, MA). Instrument All MS experiments were carried out on a LTQ mass spectrometer (Thermo Fisher Scientific, Waltham, USA). Typical instrumental parameters included 1 microscans, 15 ms maximum ion injection time, 275 °C capillary temperature, and ± 110 V tube lens voltage. Mass spectra were recorded and processed using Xcalibur software supplied with the mass spectrometer. The capillary voltage was blocked with a rocker switch to prevent damage of the electrical device from discharge. SDDBDI-MS analysis i) SDDBDI source. A detailed description of SDDBDI is given elsewhere.25 All the operation parameters for HeSDDBDI and Ar-SDDBDI were the same except the discharge gases applied. Briefly, a nanotip was used as discharge electrode and the MS inlet was ground electrode (Figure 1a). The nanotip was placed to align with the MS inlet. A piece of cover slip was used as the dielectric barrier (0.3 mm) as well as the sample-deposited surface. A custom-designed PEEK nozzle (o.d., 3 × 2 mm; i.d., 2 × 1 mm) was used to introduce the discharge gases (He or Ar). The flow rate of discharge gas was 0.6 L/min. The distance of the nanotip to the MS inlet was 3 mm. The nozzle-to-glass and nozzle-to-axis distances were 0.5 and 1.5 mm, respectively. An alternating high voltage of 4 kV with a frequency of 63.5 kHz was applied between the nanotip and the MS inlet to generate a plasma. The nanotip also held a DC offset of 200 V (Lion, HV-502P2, Tianjin, China) to guide the positive ions into the MS inlet, and vice versa. The sample

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surface was prepared by pipetting 2 µL of methanol/water (v/v: 1/1) containing analytes onto the slip surface and allowing it to dry at room temperature. To control minimal fragmentations, the voltage of 4 kV was used in the present work, and further decreasing the voltage would cause the plasma unstable. ii) Dopant introduction. A polyetheretherketone (PEEK) Tpiece tube was attached to the discharge gas tube of the SDDBDI source to introduce the dopants. A schematic of the connection is shown in Figure 1b. A syringe pump (model SP 100i, WPI, Sarasota, FL) was used to infuse organic dopants at a flow rate of 25 µL/min through a PEEK tube (o.d., 1.6 mm; i.d., 0.13 mm). The gaseous dopants were transferred by a Teflon tube (o.d., 3.2 mm; id., 2.1 mm) at a flow rate of 0.05 L/min controlled with a rotameter. Prior to sample analysis, maintaining the dopant/argon gas between the MS inlet and dielectric barrier was needed.

Figure 1. Schematic diagram of (a) SDDBDI and (b) dopants introduction.

iii) SDDBDI imaging. SDDBDI with a 2D moving stage (Chuo Seiki, Ko̅chi, Japan) was set up for imaging an “H” character. A total of 4 µL of methanol/water (v/v: 9/1) containing L-lysine (0.5 µg) and capsaicin (3.0 µg) was drawn on a glass surface, generating the “H” character. The sample surface was scanned in horizontal rows separated by 100 µm vertical steps until the entire sample had been analyzed. The character was scanned with a rate of 100 µm/s, and a total area of approximately 7 × 7 mm2 was scanned. The spectra were collected under positive ion mode using the Xcalibur software. Data were manually exported and plotted in a false-color using Origin Pro 11.0. RESULTS AND DISCUSSION Effect of discharge gas on fragmentation Fragmentation has been found in DBD with He as discharge gas for some compounds.8,22,26 A shift to argon (Ar) was performed to determine whether it could generate less fragmentation than that of using He. As shown in Figure 2a, Ar-SDDBDI produced an intense protonated sulfamethoxazole peak (m/z 254) with negligible fragmentation, while the abundance of the fragment ([M - C6H5NO2S + H]+, m/z 99) was up to 32% with He applied. Taking metronidazole as another example, He-SDDBDI spectrum showed protonated metronidazole (m/z 172) along with a distinct fragment at m/z 128 ([M - C2H4O + H]+) (Figure 2b). In comparison, Ar-SDDBDI showed minor fragmentation for metronidazole, as displayed in Figure 2b.


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Analytical Chemistry Other antibiotics were also tested with He or Ar applied. Fragmentation was significantly reduced when Ar was applied, allowing us to quickly assign the parent ions (Table S1). Fragmentations could also be suppressed in Ar atmosphere by operating DART.27 Therefore, SDDBDI of applying Ar produces intact analyte ions with little to no fragmentations and simplifies the spectra interpretation, although it has disadvantage of low sensitivity (Figure 2) that has also been reported with LTP28 and DART.27 Admixture of dopants into Ar could improve the sensitivity as will be shown below.

H2S have lower IEs than Ar* (Table S3), additional Penning ionization23,29 in Ar plasma occurs by replacing the water with dopants, resulting in the improvement of sensitivity. The signal intensity obtained by admixture of NH3 or H2S into Ar was comparable or even higher than that obtained from He (Figure 2 and 3). These results above demonstrate that the dopants examined in the present study can significantly enhance the signal intensities of analytes. However, these dopants have no significant influence on He-SDDBDI analysis (Table S4). This may be due to that the metastable helium (He*) has an IE of 19.8 eV, which can ionize impurities (e.g., O2, N2) directly for further analytes ionization.30

Figure 2. SDDBDI mass spectra of (a) sulfamethoxazole (0.3 µg) and (b) metronidazole (0.3 µg). The black and red spectra represented He and Ar used as discharge gas, respectively.

Figure 3. Effect of dopants on Ar-SDDBDI MS signals obtained from sulfamethoxazole (0.3 µg) and metronidazole (0.3 µg). (a) Organic solvents; (b) gaseous dopants. Signal intensities of protonated sulfamethoxazole (m/z 254) and metronidazole (m/z 172) were used to determine the increased MS signal, respectively. Data points are the mean values of three determinations.

Admixture of dopants into Ar-SDDBDI i) Organic solvents. A series of experiments with sulfamethoxazole and metronidazole measurements were performed to demonstrate that the combination of organic solvents with Ar-SDDBDI strategy could boost the MS sensitivity. Organic solvents such as proton acceptors (acetonitrile, methanol, ethanol, acetone, 2-propanol), benzene derivatives (toluene, fluorobenzene), and chlorinated methane (dichloromethane) were investigated, and the results are shown in Figure 3a. The observed differences among them are significant. Acetone, toluene, fluorobenzene, methanol, ethanol, and 2propanol enabled 1−2 orders of magnitude increase in signal intensity. This is due to that their ionization energies (IEs) (Table S2) are lower than that of metastable argon (Ar*) (11.5 eV), resulting in additional Penning ionization in Ar plasma. However, acetonitrile and dichloromethane almost have no influence on the signal intensity. This is probably because of their high IEs of 12.2 and 11.3 eV, which cannot be efficiently ionized by Ar*. These two dopants were also unfavorable for Ar-DART.27 ii) Gaseous dopants. Gaseous dopants such as NH3 and H2S were also selected for testing. In Figure 3b, an enhancement on the signal intensity for all samples tested was found as a result of adding NH3 and H2S into Ar. Because NH3 and

Probable Reactions in dopant/Ar-SDDBDI Scheme 1 describes a series of reactions to explain the be havior that the signal intensity increased approximate 1−2 orders of magnitude with organic and gaseous dopants applied. When the applied dopant (D) has lower IE than Ar*, dopant substituting for water in Ar plasma undergoes Penning ionization(Reaction 1) followed by proton transfer to produce protonated dopant clusters (Reaction 2). This was confirmed by the mass spectrum of ethanol in Ar plasma, in which the Scheme 1. Probable reactions in dopant/Ar-SDDBDI.



Figure 4. Pharmaceutical analysis using ethanol/Ar-SDDBDI. (a) He and (b) ethanol/Ar as discharge gas for guaiacol (1.3 µg). (c) He and (d) ethanol/Ar as discharge gas for propazine (2.3 µg).

[EtOH + H]+, [(EtOH)2 + H]+, [(EtOH)2 - H2O + H]+ and [(EtOH)3 + H]+ peaks are dominant (Figure S1). The analyte molecule (M) is then ionized to form protonated molecule by gas-phase ion/molecule reaction with the protonated dopant molecule (Reaction 3). Methanol, ethanol, and acetone are examples, because their PA(D) values are higher than their (D−H) radicals (Table S2). The analyte molecule (M) can also be directly ionized by dopant molecular ion to generate protonated molecule (Reaction 4). Evidence to support this reaction is the case of fluorobenzene, who has a lower PA value than its (D−H) radical, as shown in Table S2. The similar results have been reported for DART.27,31 Performance of dopant/Ar-SDDBDI i) Pharmaceutical Analysis. As a demonstration, guaiacol and propazine were analyzed by He- and dopant/Ar-SDDBDI. For convenience and safety consideration, ethanol was selected as a model dopant in this work. The resulting spectra are shown in Figure 4. Figure 4a and 4b depict the results of guaiacol with He and ethanol/Ar applied, respectively. In the case of He analysis, two fragment signals at m/z 109 and 95 corresponding to [M – O + H]+ and [M - CH2O + H]+ were intense, whereas in the case with ethanol/Ar applied, these two fragments completely disappeared and the spectrum was dominated by protonated guaiacol (m/z 125). These two fragments have been reported with He-LTP where using a plasma plume direct at the guaiacol deposited on an adhesive tape.22 Propazine is another sensitive compound for He-DBDI in the positive ion mode. It generally shows two characteristic fragments with m/z 188 and 146 associated with [M - C3H6 + H]+ and [M - C6H12 + H]+.26 Ionization using He-SDDBDI also produced these two fragments, as shown in Figure 4c. As expected, the fragmentation was suppressed in the case of ethanol/Ar, and thus assignment of protonated propazine (m/z 230) was very convenience (Figure 4d). Furthermore, the signal intensities attainable by ethanol/Ar for guaiacol and propazine were comparable or even higher than that obtained by He. ii) Biological Molecules Analysis. Ethanol/Ar-SDDBDI can also be greatly beneficial for applications in analysis of biological molecules. Figure 5a and 5b show the positive mass spectra of L-lysine and L-serine, respectively. The major signal in each case was the [M + H]+ peak, and only limited fragmentations were observed. Distinct fragmentations in the analysis of amino acids were observed using plasma-based

methods such as He-DBDI8 and He-SDDBDI (Figure S2a and S2b). In addition, results of other amino acids tested with ethanol/Ar were listed in Table S5. Decreased fragmentations and comparable sensitivities were obtained in comparison with He-DBD.8 In the mass spectrum of cis-7-octadecenoic (18:1) acid methyl ester (Figure 5c), protonated signal at m/z 297 was very intense. A fragment peak at m/z 159 was detected at low abundance. This fragment corresponded to protonated forms of the aldehyde oxidation products retaining the ester chain, and can be used to unequivocally assign double bond locations in monounsaturated fatty acids containing simple methyl or ethyl esters. However, this is contrasted with the spectrum using HeLTP where the signal at m/z 159 is the base peak.32 Besides detection of monounsaturated fatty acid, ethanol/Ar-SDDBDI is also capable of ionizing polyunsaturated fatty acids. This was demonstrated by analysis of pinolenic acid (18:3) ethyl ester. Ionization using ethanol/Ar-SDDBDI produced an intense signal at m/z 307, which is associated with protonated pinolenic acid ethyl ester. Peaks of m/z 199 and m/z 239 were assigned as ester-containing aldehyde oxidation products. Note that these fragment peaks were detected at low abundances, but they are evident in the spectra using He-LTP32 and HeSDDBDI (Figure S2c and S2d). Further tests were done using ethyl palmitate and myristic acid in the positive and negative ion mode, respectively. The results show that the fragmentations with He are significantly suppressed in the case of ethanol/Ar (Figure S3). Besides, peptides and lipids were also tested using He, Ar, and ethanol/Ar as discharge gases. For peptides, fragmentation was significantly suppressed with ethanol/Ar applied, which was abundant in the corresponding mass spectra when He was used as discharge gas (Figure S4). However, no signals of lipids listed in Table S6 were observed (data not shown). To our best knowledge, little data about lipids were available using the nonthermal plasma methods (DBDI and LTP).14,30 This may be related to the poor desorption, which could be improved by heating the gas or sample plate.26,33 iii) Complex matrixes analysis. The utility and convenience of using ethanol/Ar-SDDBDI approach for rapid profiling of mixtures were demonstrated by direct analysis of the chemicals in such complex matrixes including drug tablets. Tablets of the acetaminophen and ibuprofen were analyzed in


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Analytical Chemistry

Figure 5. Biological molecules analysis using ethanol/Ar-SDDBDI. Mass spectra of (a) L-lysine (0.5 µg), (b) L-serine (0.5 µg), (c) cis-7octadecenoic (18:1) acid methyl ester (3.0 µg ), and (d) pinolenic acid (18:3) ethyl ester (3.0 µg).

the positive ion mode. As shown in Figure 6, protonated acetaminophen (m/z 152) and ibuprofen (m/z 207) are the most abundance species. The reported results obtained by using other plasma-based techniques showed that the product ions of acetaminophen and ibuprofen were not consistent. As an example, acetaminophen can be ionized in He plasma using DBDI, DART and rf glow discharges.34 However, a fragment peak at m/z 109 corresponding to [NHC6H4OH + H]+ was observed with all three sources. Ionization of ibuprofen with PADI using He as discharge gas produced protonated ibuprofen at m/z 207 and a evident fragment of m/z 161 ([M COOH + H]+).10 In another study, ibuprofen was ionized using He-DBD, resulting in ammoniated ibuprofen monomer and protonated dimer as well as trimer.35 It is well-known that small molecules tend to polymerize in He plasma when using DBD.17

Figure 6. Ethanol/Ar SDDBDI mass spectra of complex mixtures: (a) acetaminophen tablet (1.5 µg) and (b) ibuprofen tablet (2.0 µg).

The capability of the ethanol/Ar-SDDBDI to analyze samples in complex matrixes has been further demonstrated by a mixture of biologically relevant compounds such as octopamine, 5-hydroxytryptamine, and normetanephrine in positive ion mode with He or ethanol/Ar used as discharge gas. A comparison of the mass spectra in Figures S5a and S5b shows that the protonated signals were observed without any interference in the case of ethanol/Ar. Besides being operated in positive ion mode, ethanol/Ar-SDDBDI is also suitable for operation in negative ion mode. This was demonstrated by analysis of a mixture of glucose and ferulic acid. As shown in Figures S6a and S6b, He-SDDBDI spectrum showed evident fragments, whereas in the ethanol/Ar spectrum only protonated signals were observed. These results indicate that ethanol/ArSDDBDI has advantages of interpreting a mixture involving fragile compounds with little to no fragmentations in both positive and negative ion modes. iv) Limit of detection. The limit of detection (LOD) of ethanol/Ar-SDDBDI-MS was investigated by analysis of Lalanine and metronidazole. Calibration curves of L-alanine and metronidazole were estimated by plotting intensity of protonated L-alanine (m/z 90) and metronidazole (m/z 172) versus the concentration, respectively. As shown in Figure S7, a good correlation coefficient (R2) of 0.98 was obtained with a dynamic response range of 2 orders of magnitude. The LODs (S/N = 3) of L-alanine and metronidazole were determined to be 0.60 pmol and 0.36 pmol, respectively, which are comparable to those obtained by He-SDDBDI25 and He-DBDI8,18. Mass spectrometry imaging Another feature of the ethanol/Ar-SDDBDI approach is that it can be used to locate the distribution of fragile compounds. As a proof-of-principle experiment, imaging of an “H” character was performed. Figure 7c depicts the optical image of the character after drying at room temperature. When the microplasma crossed an individual pixel, signals of protonated Llysine and capsaicin at m/z 147 and 306 were clearly observed in the ethanol/Ar-SDDBDI spectrum (Figure 7b). This is contrasted with He-SDDBDI spectrum where the protonated molecules along with evident fragments were observed (Figure 7a).



The intense peak of m/z 130 was formed by loss of NH3 from protonated L-lysine, and m/z 137 was a characteristic fragment of capsaicin. These fragments were commonly observed when using conventional DBDI8 and LTP.21 Figure 7d, e shows the MS images of the signals associated with m/z 147 and 306, respectively. The ion signals clearly show the profile of the “H” character.

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ASSOCIATED CONTENT Supporting Information Mass spectrum of ethanol in argon plasma, positive and negative spectra of complex mixtures, analysis of antibiotics under different discharge gases, characterization of organic and gaseous dopants, and detection of amino acids, fatty acid, and peptides with ethanol/Ar applied. AUTHOR INFORMATION

Corresponding Author *E-mail: [email protected]. Fax: + (86)-631-5685-359; Author Contributions Hong Zhang and Jing He contributed equally to this work.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS This work was supported by the National Key R&D Program of China (2016YFF0100302), National Natural Science Foundation of China (21705030), and Natural Science Foundation of Shandong (2016YYSP013, ZR2016BM11, ZR2016BP01). We sincerely thank our teammates Wenhai Wu for fabrication of the SDDBDI source and other relevant parts, Jing Gao for helping with the production of the electronic for the plasma source, and Hengnan Zhang for helping the control of the 2D moving stage.

REFERENCES Figure 7. Ethanol/Ar-SDDBDI imaging. Mass spectra of an individual pixel using (a) He or (b) ethanol/Ar as discharge gas; (c) optical image of the character H; ethanol/Ar-SDDBDI images of (d) m/z 147 and (e) m/z 306, pixel size was 100 × 100 µm.

CONCLUSIONS In conclusion, by combining of Ar-SDDBDI with dopants, rapid profiling of liable compounds with high signal intensity and little to no fragmentation has been achieved. The dopants ranging from organic solvents to gaseous materials for improving MS sensitivity were systematically studied, providing a guidance for better understanding of the microenvironment in argon plasma. The analytes were ionized primarily through proton transfer with dopant ions. Methanol, ethanol, acetone, 2-propanol, toluene, fluorobenzene, NH3, and H2S were favorable dopants for Ar-SDDBDI ionization. Fragmentations were suppressed with dopant/Ar-SDDBDI. This offers further benefit for differentiating the analytes from the fragments. Positive and negative mass spectra with little to no fragmentation were readily obtained, for the analysis of antibiotics, pharmaceuticals, amino acids, fatty acids, and such complex matrixes including mixtures and drug tablets. The LOD was determined to be 0.60 pmol for L-alanine and 0.36 pmol for metronidazole. Because of direct imaging capability of SDDBDI, imaging of compounds under ambient conditions was successfully achieved. All these capabilities bring opportunities to analyze compounds that are prone to fragment using He in MSI with high signal intensity, high spatial resolution, and very low degree of fragmentation. Moreover, this dopant/Ar-SDDBDI approach has desirable features for studying the fragile compounds in biological and related subjects.

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