Multifunctional Carbon Fiber Ionization Mass Spectrometry

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Multi-functional Carbon Fiber Ionization Mass Spectrometry Meng-Xi Wu, HaoYang Wang, Jun-Ting Zhang, and Yinlong Guo Anal. Chem., Just Accepted Manuscript • Publication Date (Web): 08 Sep 2016 Downloaded from http://pubs.acs.org on September 8, 2016

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Analytical Chemistry

Multi-functional Carbon Fiber Ionization Mass Spectrometry Meng-Xi Wu, Hao-Yang Wang*, Jun-Ting Zhang, Yin-Long Guo* State Key Laboratory of Organometallic Chemistry and National Center for Organic Mass Spectrometry in Shanghai, Shanghai Institute of Organic Chemistry, CAS, 345 Lingling Road, Shanghai, China, 200032 ; [email protected], [email protected] ABSTRACT: A carbon fiber ionization (CFI) technique was developed for the mass spectrometric analysis of various organic compounds with different polarities. The design of the CFI technique was based on the good compatibility and dispersion of samples and solutions in different solvents on carbon fiber. As a fast, convenient and versatile ionization method, CFI-MS is especially efficient for analyzing many low/non-polar organic compounds, such as polycyclic aromatic hydrocarbons, long-chain aliphatic aldehydes, sensitive steroids, terpenoids and organometallic compounds. Some of these compounds may not be well-analyzed by electrospray ionization or electron ionization mass spectrometry. Based on our experimental results, the major ion formation mechanism of CFI-MS was suggested to involve desorption in a steam-distillation-like process, and then, ionization occurred mainly via corona discharge under high voltage. CFI-MS could not only work alone but could also be coupled with separation techniques. It works well when coupled with supercritical fluid chromatography (SFC) as well as in the analysis of exhaled human air. The high flexibility and versatility of CFI-MS has extended its applications in many areas, such as fast chemical screening, clinical testing and forensic analysis.

M

ass spectrometry (MS) is one of the most powerful chemical analysis technologies and is gaining increasing interest in numerous fields.1-4 Recent progress in MS has depended to a large extent on advances in the methods of ion formation. An ionization device that has fewer analysis restrictions and better compatibility with different samples is greatly needed. Electrospray ionization (ESI)5-8 and atmospheric pressure chemical ionization (APCI)9-12 are two ionization methods that are currently widely used. Recently, many ambient ionization techniques based on ESI and APCI mechanisms have been developed, such as desorption electrospray ionization(DESI),13 direct analysis in real time (DART),14 extractive electrospray ionization(EESI),15 and ambient flame ionization.16 These ambient mass spectrometric methods allow samples to be analyzed in their native states with much less sample preparation. Among them, the substrate spray methods, which rely on a spray-based ionization mechanism from substrates, including paper spray ionization (PSI),17-19 wooden tip ionization,20 leaf spray ionization,21 etc., further extend the applications of MS in sampling difficult-toaccess samples and for the direct analysis of biological tissues and fluids. With this body of knowledge and some important reviews,22-24 the research in this field has progressed rapidly. Although the newly developed ambient ionization methods have largely simplified analytical procedures and improved ionization capabilities, the highly efficient mass spectrometric analysis of low/non-poplar and sensitive organic compounds still remains a large challenge. Compounds such as terpenoids and long-chain aliphatic aldehydes are difficult to detect by ESI/APCI-MS due to their relatively low ionization efficiencies. Additionally, some of these compounds are highly fragile, which mainly leads to the formation of fragment ions due to the harsh conditions in APCI-MS and electronionization (EI)-MS analysis. These fragment ions increased the

difficulty for direct quantitative and qualitative analyses of these compounds by mass spectrometric methods. Herein, an ionization technique based on a carbon fiber (CF), called carbon fiber ionization (CFI), was designed and shown to solve such challenging problems. CFI-MS is an easily built device involving a removable modular CF probe in front of a mass spectrometer (Figure 1a), an adjustable high voltage DC supply applied to the CF probe, and an optional solvent delivery system feeding assisting solvent or transferring effluents from separation techniques. CFI-MS works quite well without heating or pneumatic assistance. The CF used here is a material consisting of fibers approximately 5–10 µm in diameter composed mostly of carbon atoms.25,26 The properties of CFs, such as high stiffness, high chemical resistance and high temperature tolerance, make them very popular and widely used. The good adsorptive properties of CFs have allowed them to be used as solid-phase exaction devices.27 However, they were rarely used as an ionization material except for in the reforming of ionization devices such as in ESI emitters by Knapp’s group.28, 29 Various other ESI emitters, such as copper wires,30 metal needles31, 32 and optical fibers wired with a metal coil33, improved the sampling and ionization processes, facilitating the analysis of various types of samples. In this study, CFs play the dominate role in sampling and achieving desorption/ionization. Therefore, CFIMS has a different ion generating mechanism than the above methods, which are mainly based on helping electrospray ionization. Additionally, with the help of multi-functional CFs, different sampling and working modes can be used, thus greatly expanding the applications of CFI-MS.

EXPERIMENTAL SECTION All of the materials used are commercially available. Detailed information about the chemicals and materials is listed in the Supporting Information.

ACS Paragon Plus Environment


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Figure 1. (a) Photograph of a CFI-MS device. (b) Quantitative analysis of L-lysine with the internal standard (4,4,5,5-d4) L-lysine (10 µg·mL-1) by CFI-MS in the probe mode. Analyte concentrations of 1-100µg·mL-1 was used. Error bars represent the standard deviation of analyses for three replicates with independent CF probes. (c-f) CFI-MS spectra in the probe mode: (c) lipid sample, 2-dimyristoleoyl-snglycero-3-phosphocholine (20 µg·mL-1, methanol/water (1:1, v/v) solution), showing the protonated molecule of m/z 674 with the MS/MS spectrum (as inset), (d) sensitive steroid (cholesterol) (10 µg·mL-1, methanol solution), showing the intact ion [M+H]+ of m/z 387 and [MH2O+H]+ of m/z 369, (e) volatile terpenoid (ocimene) (1 µg·mL-1, n-hexane solution), showing the protonated molecule of m/z 137, and (f) ferrocene (10 µg·mL-1, toluene solution), showing its radical cation of m/z 186.

CFI-MS conditions. The CFI device consists of a removable modular CF probe (a small bunch of carbon fibers of 0.5-1 cm in length and 3000 tows immobilized tightly in between 2 steel tubes with the other end of the tube having a polyetheretherketone (PEEK) adaptor), an assisting solvent flow control system (feeding solvent via the PEEK tube connected to the CF probe by the adaptor and the CFI-MS could also operate in solvent-free mode) and a high voltage supply (approximately 2.5 kV) applied on the CF with a clip on the steel tube to ionize analytes and transfer the ionic species into the mass spectrometer (Figure 1a). The ionization current in the CFI-MS was measured at the 0-1 µA level. The detailed installation method, properties of the CF and the optimization of the CFI-MS conditions (voltage, flow rate/volume, type of solvents, distance to the MS inlet and CF conditions) are summarized in the Supporting Information. Three different main sampling and working modes of CFIMS analysis can be used including the probe mode, interface

mode and collector mode (Figure 2). In the probe mode (a), the CF probe serves as an ionization substrate, and a small amount of sample solution (typically 2 µL, concentrations of 0.5-10 µg·mL-1, total amount of 1-20 ng) can be preloaded onto the carbon fiber by a micropipette for direct testing. CFIMS allowed direct detection in a short time (less than 0.5 minutes) and with a minute amount of analyte without requiring separations or complicated procedures. In the interface mode (b), CF acts as the interface of a mobile phase and the MS inlet for continuous CFI-MS analysis. The mobile phase can be liquid, gaseous or even a supercritical fluid (SCF). Due to the unique characteristics of the CF, there are also no clogging problems, making the CFI technique an ideal interface for liquid chromatography (LC) or other related separation techniques with MS. In the collector mode (c), the CF probe, which has good adsorptive properties, can be easily taken off and used as a soft brush to gently sweep certain surfaces, hidden corners and even to directly immerge in bulk


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solutions to collect suspected compounds, and then, it can used for subsequent CFI-MS analysis. Therefore, the CFI-MS combined sample collection and ionization process simplified the operation steps and saved analysis time.

Figure 2. Schematic illuminations of the three working modes of CFI-MS. The removable modular CF probe is the core component of the CFI device. (a) Probe mode, direct MS analysis with several microliters of sample solution preloaded onto the CF probe or releasing vapors of volatile compounds around the CF probe (without an assisting solvent). (b) Interface mode, working in the continuous flow mode to analyze effluents from the separation techniques. (c) Collector mode, the modular CF probe could be removed to collect samples from corners, liquids or surfaces. After an enrichment step, the modular CF probe was reloaded for MS analysis.

Instrumentation. The CFI-MS and subsequent MS/MS measurements were carried out using a Thermo TSQ Quantum AccessTM triple-quadrupole mass spectrometer (Thermo-Fisher Scientific, Waltham, MA, USA). The exact mass measurements were performed with a linear ion trap-Fourier transform ion cyclotron resonance mass spectrometer (LTQFT MS, Thermo-Fisher Scientific, Bremen, Germany). Unless otherwise specified, positive-ion mode CFI-MS was used during our experiment. SFC-MS analysis was performed using a Shimadzu Nexera UC Supercritical Fluid Chromatograph (Nexera UC, SFC) and an LCMS-8040 mass analyzer (Shimadzu (China) Co., Ltd., Kyoto, Japan). SFC-ESI-MS was operated in the following conditions: injection volume, 5 µL; supercritical carbon dioxide (SCCO2) flow rate, 0.5 mL·min-1; and 50% addition of CH3OH. For CFI-MS, the SCCO2 flow rate was 0.5 mL·min-1 with the addition of 5% CH3OH.

RESULTS AND DISCUSSION Initial experiments were performed to demonstrate the capacity and scope of application of CFI-MS by analyzing various compounds with different polarities, such as amino acids, phosphocholine, volatile terpenoids, PAHs, organometallic compounds and steroids. Most compounds showed high-quality CFI-MS spectra in the probe mode (Figure 1c-f and Figure S-8 in the Supporting Information). Negative ion mode CFI-MS spectra can also be obtained when a high negative voltage (also approximately 2.5 kV) was applied (see Figure S-9). Quantitation of L-lysine was achieved in probe mode CFI-MS and is shown in Figure 1b. The intensity ratio of the analyte (lysine, [M+H]+, of m/z 147) to the internal standard ((4,4,5,5-d4) L-lysine, 10 µg·mL-1, [M+H]+, m/z 151) plotted against the lysine concentration was linear across a concentration range of 1-100 µg·mL-1. Another significant advantage of CFI-MS is the broad solvent compatibility. Many non-polar and non-ESI friendly solvents34-36 (e.g., toluene and hexane) can also be used in CFI-MS, showing great convenience and tolerance in the

analysis of non-polar analytes and solutions in non-polar solvents. Coupling SFC with CFI-MS. Supercritical fluid chromatography (SFC),37-39 in which an SCF is used as the mobile phase, is characterized by high resolution at high flow rates; hence, it is gaining interest and is widely used. One of the most commonly used mobile phases in SFC is SCCO2 due to its non-toxic nature, non-reactivity, low cost and ease of handling. However, SCCO2 has a low polarity similar to hexane, and thus, its elution power should be varied by adding a modifier (e.g., methanol) before it can be analyzed by ESIMS.40 The additional pumping or flow splitting complicated the experimental conditions. Moreover, non-polar and thermally unstable analytes, two of the most common fields of application of SFC, cannot be easily ionized by ESI and APCI, respectively. Meanwhile, the fact that hexane and other nonpolar solvents work well with CFI-MS inspired us to use CFIMS in the detection of SFC effluents. Four different kinds of sample solutions (methyl salicylate, ocimene, 2-methyl-1pentanone and anthracene) were tested in CFI-MS and ESIMS. No corresponding signals were observed in positive-ion mode ESI-MS analysis, even when the percent of CH3OH in SCCO2reached 50%. Meanwhile, all 4 compounds display high-quality MS spectra in CFI-MS positive-ion mode with only 5% CH3OH added to SCCO2 (Figure 3), showing the potential of CFI-MS for direct analysis of low/non-polar and sensitive SFC effluents.

Figure 3. Interface mode CFI-MS spectra of 4 different types of SFC effluents: (a) methyl salicylate (ethanol solution); (b) ocimene (ethanol solution); (c) 2-methyl-1-pentanone (water solution); and (d) anthracene (toluene solution). The concentration of the samples was 0.1 mg·mL-1.

Human breath analysis. The good compatibility of CFIMS with gaseous fluid and volatile molecules can also be used for the analysis of air exhaled by humans. Analysis of trace constituents in exhaled gas can provide useful insights into biochemical processes and revealing information about metabolic dynamics.16 Previously, proton transfer reaction mass spectrometry and selected ion flow tube mass spectrometry have been used for direct breath analysis, but these techniques require specially designed instruments that are not widely available. EESI-MS1 established by Zenobi and co-workers achieved rapid and direct analysis of breath, inspiring us to explore the application of CFI-MS in this new field. A preliminary experiment was performed to qualitatively analyze some volatile compounds in air exhaled by humans. The breath (approximately 5 minutes after smoking) of a male smoker was investigated using CFI-MS by directly exhaling towards the operating CF probe through a straw (probe mode).



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The analysis showed the presence of nicotine ([M+H]+, m/z 163) and cotinine (the important metabolite of nicotine, [M+H]+, m/z 177), which are associated with smoking as shown in Figure 4. This part of the work was just a preliminary study, which showed the capacity of CFI-MS for the direct analysis of exhaled air. Further studies will be carried out, and attempts will be made to analyze some other types of compounds in human breath to help in clinical diagnosis.

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MS/MS for the ion of m/z150 (see Figure S-10 c-d). Moreover, a limit of detection (LOD) of approximately 10 pg·mL-1 was achieved for N,N-diethyl-3-methylbenzoylamide43 in a water/ethanol (1:1, v/v) solution (see Figure S-11 and Table S4). Trace volatile vapor can also be detected directly as shown in Figure S-12. The flexible sampling/working styles and good sensitivity of the CF probe help the direct characterization of samples on surfaces, in biofluids or in other complex mixtures without sample pretreatment, making CFI-MS collector mode analysis a superior candidate for fast chemical screening in clinical drug monitoring, criminology and forensics. This also enables MS imaging techniques, in which different areas of a surface can be detected separately to visualize the spatial distribution of chemical compositions, which will be studied further in the future.

Figure 4. (a) Probe mode CFI-MS spectrum of breath 5 minutes after smoking. Nicotine ([M+H]+ of m/z 163) and one of its main metabolites cotinine ([M+H]+ of m/z 177), which are associated with smoking, were found, and the enlarged partial spectrum at m/z 100-250 is shown below (b).

Surface and bulk solution analysis. Eberlin et al. highly praised the application of ambient MS in forensic science with the words “a perfect couple destined for a happy marriage” and anticipated that many beneficial and matching figures of merit will bring forensic chemistry and ambient MS into a long-term relationship.41, 42 Here, CFI-MS provides us an effective method to help consolidate this relationship. CFIMS in the collector mode could reduce the sample pretreatment steps by combining the sample enrichment and CFI-MS analysis in one single device and thus have great potential in assisting forensic science. In a simulated crime scene of surfaces exposed to illicit drugs, small amounts of illicit drugs (2 µL of methane solution containing 50 ng samples dropped in areas of 1 cm2) can be collected by the CF probe sampler. With the help of an assisting solvent and a high voltage, protonated ketamine (m/z 238) and pethidine (m/z 248) can be detected directly by CFI-MS (see Figure S-10 ab). Another convincing example is the utilization of CFI-MS in rapid urinalysis, which is one of the most convenient and valid ways to judge whether a person is a drug abuser. CFIMS is also a rapid and simple way to directly analyze illicit drugs in urine without any sample pretreatment. A small amount of methamphetamine was added into undiluted human urine (0.1 µg·mL-1). After dipping the removable CF probe into 1 mL of urine sample for seconds, CFI-MS spectra were recorded. Other than the ions related to some endogenous compounds in urine, such as urea and creatinine, the protonated molecule of methamphetamine of m/z 150 was detected, and its chemical identity was confirmed with CFI-

Figure 5. (a) ESI-MS, (b) APCI-MS, (c) EI-MS and (d) CFI-MS spectra of dodecanal (n-hexane solution, 10 µg·mL-1) in the positive ion mode. The protonated molecule of m/z 185 can only be observed by CFI-MS.

According to Millikan,44 non-polar solvents are not successfully applied in ESI without a mixture of polar solvents45-47 or ionic liquids. As for ESI-MS, both the ionic species formation step and the following step of transferring the ionic species to the gas phase environment are seriously dependent on the properties of the solvent. However, as described previously, most solvents could be used in CFI-MS analysis, and there is no limitation on the electrical conductivity, boiling point or polarity of the solvent applied in


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CFI-MS. According to Zare, Chen et al.,48, 49 MS is a powerful tool in directly analyzing the short-lived intermediates of organic reactions, and the unique characteristics of CFI-MS allowed direct analysis of solutions prepared in various solvents without an assistant solvent or the addition of extra reagents to enhance the ionization efficiency, making CFI-MS an ideal method for the fast monitoring of a reaction by direct detection of the reaction solutions.50, 51 A primary experiment was performed, showing that online derivatization can be achieved conveniently by the derivatization reaction on the CF probe (see Figure S-13). Other than solvent choices, CFI-MS showed a higher ionization efficiency and softer character than some other ionization methods. For example, dodecanal, as a low-polarity long-chain aliphatic aldehyde, showed no obvious [M+H]+ signals in ESI or APCI-MS and mainly formed fragment ions in EI-MS (Figure 5a-c). Rather amazingly, CFI-MS gave clear signals of the protonated molecule of m/z 185 (Figure 5d). PAHs, terpenoids, steroids and many other compounds that cannot be efficiently ionized by ESI can yield satisfactory results by using CFI-MS (see Figure S-14). Ion formation mechanism of CFI-MS. After revealing all of these important applications, CFI-MS was compared with several widely used ionization techniques to seek an explanation for its ion generating mechanism. First, we found that peptides and proteins cannot be detected directly by CFIMS because of the failure of desorption due to the strong adsorption of peptides and proteins on the CF probe (see Figures S-15 and S-16). The non-volatile sodium or potassium salts and quaternary ammonium salts only show signals at obvious high concentrations when polar solvents were applied (see Figure S-17). The major ionization mode of CFI-MS is protonation. Na or K adduct ions are rarely observed - they were only observed in Figure S-13.These results suggested that CFI-MS might have a different ion formation process than that in electrospray-based methods. The electrospray-based mechanism of CFI-MS could not be excluded, and an electrospray-like process may occur in some circumstances, especially when polar solvents were used. Overall, the major ionization behaviors of CFI-MS share more similarities with the APCI mechanism, where the corona discharge plays the dominant role in ionization. Therefore, an APCI-like process was proposed as the major ion formation mechanism of CFI-MS and involves the following two steps: desorption followed by ionization. According to the proposed mechanism, the first step of ion formation of CFI-MS is the desorption step of organic compounds from the CF probe by a steam-distillationlikeprocess.52 The solvent vaporization in this gentle process could promote the desorption of analytes from the CF probe, and such an effect has been studied and discussed by Eberlin and Dupont.52 The experimental results that volatile compounds can be directly ionized without loading any solvents supported this hypothesis. The drifting vapors of these volatile compounds, including ocimene, butyrophenone and 1-hydroxy-7-azabenzotriazole, were detected by CFI-MS approximately 20 cm from the dry CF probe without solvent pre-wetting of the CF probe, showing intensive [M+H]+ signals (Figures S-18 and S-19). The second step is the ionization of the desorbed molecules via room temperature corona discharge. According to this mechanism, the solvent is not critical for the ionization process, and our experiments

supported such a hypothesis, which showed that the proton source in the ion formation process of CFI-MS was mainly from the nearby gaseous atmosphere and not the solvent (see Supporting Information: Experiments for the determination of the proton source during CFI-MS ionization). When other types of carbon fibers with different properties were applied and surface/structure modifications or coatings were performed, the ionization mechanism might also change. This will be studied in our further studies. The major role of solvent in CFI is not in the formation of the charged droplets and further release of ionic species by coulombic explosion in a concerted process, especially when low/non-polar solvents were applied. The solvents applied in CFI-MS play an important role in the desorption step by sample evaporation or solvent delivery and reducing the discharge effects between dry CFI-MS and the MS inlet. Meanwhile, the evaporation of solvent and room temperature operating conditions of CFI-MS result in its softer ionization behavior than APCI-MS or DART-MS (see Figure S-20). By appearance, the CFI-device looks like one of the substrate spray methods53 (e.g., PSI), but great differences exist. CFI has its own working mechanism that is more similar to the room-temperature APCI. However, PSI-MS shared more similarities with ESI-MS. CFI-MS and PSI-MS showed similar results in the analysis of polar organic compounds, but CFI shows advantages in the analysis of low/non-polar analytes, especially in solutions with low/non-polar solvents. In the detection of anthracene (toluene solution), CFI showed a molecular ion of m/z 178, while PSI-MS showed no related signal under similar conditions. When a low/non-polar solvent is used, PSI can be used to ionize some types of compounds,17 but mainly polar compounds (e.g., peptides). The voltage applied is significantly higher (approximately 5 kV) than that of CFI (approximately 2.5 kV). However, PSI also has its own advantage over CFI in that peptides and proteins can be wellanalyzed, and thus, it is more suitable for tissue and biosample detections. These new ionization techniques, including CFI and PSI, were all compliments of current existing methods and have their own special fields of application. Other carbonbased materials, such as carbon nanotubes, have also been coated on paper for use as an ionization material in Pradeep’s work.54, 55 However, that is totally a different ionization mechanism, and only 3 V is needed to achieve field emission of the charged droplets. Therefore, it has different applications than the CFI-MS technique highlighted here. Another common carbon-based material is graphite wire. Our primary experimental results showed that graphite wire could also be used in a similar device as an ionization probe; however, it is too soft, not easy handling and not good at collecting samples as the removable CF probe. Moreover, the ionization performance of the CF probe is much better than that of the graphite wire ionization probe (see Supporting Information: Experiments for comparing CFI with graphite wire ionization).

CONCLUSION A CFI source was developed in this study for the rapid and direct MS analysis of various organic compounds and their solutions in different solvents. A series of experimental results showed that to a certain extent, CFI-MS shares a similar desorption/ionization mechanism with APCI. The evaporation of solvent and the room temperature operating conditions of CFI-MS lead to its many advantages, such as a simple device



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without heating or pneumatic assistance, comparably softer ionization than APCI and DART, good compatibility with various solvents, high flexibility and versatile working modes. The versatility of the CF probe expanded the scope of application of CFI-MS in many aspects in the probe mode, interface mode and collector mode. From the above demonstrations, the CFI-MS technique is believed to have desirable features for fast chemical screening in clinical and detective applications. In the meantime, CFI provides great potential for coupling with many separation techniques, such as SFC, NPLC and GC, according to its scope in the analysis of various organic compounds.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.anal-chem. Additional information is included on the assembly of the CF probe; optimized experiment conditions; details of additional experiments; mass spectra; tables; and images (PDF).

AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected]. Tel.:+86-021-54925307 (Wang, H. Y.) *E-mail: [email protected]. Tel.:+86-021-54925300 (Guo, Y. L.)

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS This work was supported by grants from the National Natural Science Foundation of China (Grant Nos. 21532005, 21475145 and 21472228) and the Youth Innovation Promotion Association CAS (No. 2013171 to H.W.).

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for TOC only


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Multifunctional Carbon Fiber Ionization Mass Spectrometry

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