Table of Contents

Cover

Title Page

Dedication

Preface

About the Editor

Chapter 1: Introduction of Mass Spectrometry and Ambient Ionization Techniques

1.1 Evolution of Analytical Chemistry and Its Challenges in the Twenty-First Century
1.2 Historical Overview of Mass Spectrometry and Its Role in Contemporary Analytical Chemistry
1.3 Desorption/Ionization in Mass Spectrometry
1.4 Ambient Ionization and Direct Analysis in Real Time
References

Chapter 2: DART Mass Spectrometry: Principle and Ionization Facilities

2.1 Introduction
2.2 Metastable Gas Stream Formation
2.3 Ionization Mechanisms in Positive DART
2.4 Ionization Mechanisms in Negative DART
2.5 Some Parameters Affecting the DART Mass Spectra
2.6 Conclusion
References

Chapter 3: Sampling and Analyte Enrichment Strategies for DART-MS

3.1 Dilution Strategy for Sticky Sample Analysis
3.2 Purification Strategy for Eliminating the Matrix Interference
3.3 Derivatization Strategy to Decrease Polarity and Enhance Volatility
3.4 Conclusions
References

Chapter 4: Optimization of DART and Mass Spectrometric Parameters

4.1 Introduction
4.2 Effect of Working Gas Type, Gas Flow Rate, and Its Temperature
4.3 Effects of Grid Electrode Voltage and Sampling Speed
4.4 Effect of the Sampling Mode
4.5 Effect of Ion Mode
4.6 Effect of Solvent Type and Reagents
4.7 Summary
References

Chapter 5: Interfacing DART to Extend Analytical Capabilities

5.1 Introduction
5.2 Interfacing DART with Different Separation Techniques
5.3 Techniques of Interfacing DART with Other Analytical Techniques
5.4 Conclusion and Perspectives
References

Chapter 6: Application of DART-MS in Foods and Agro-Products Analysis

6.1 Introduction
6.2 Applications of DART-MS in Agriculture and Food Science
6.3 Conclusion
References

Chapter 7: Application of DART-MS for Industrial Chemical Analysis

7.1 Application on Household Items
7.2 Application on Food Packaging Safety and Quality Control
7.3 Application on Pharmaceutical Products
7.4 Application on Cosmetics Quality Control
7.5 Application on Other Industrial Chemical Fields
7.6 Conclusions
References

Chapter 8: Application of Direct Analysis in Real Time Coupled to Mass Spectrometry (DART-MS) for the Analysis of Environmental Contaminants

8.1 Introduction
8.2 Screening and Quantitative Analysis of Pesticides
8.3 Flame Retardants DART-MS Analysis
8.4 Use of DART-MS for the Analysis of Personal Care Products (PCPs)
8.5 Use of DART-MS for the Analysis of Aerosols
8.6 Miscellaneous Environmental Application of DART-MS
8.7 Conclusions
References

Chapter 9: Application of DART-MS in Clinical and Pharmacological Analysis

9.1 Introduction
9.2 Sample Preparation
9.3 Applications of DART-MS
9.4 Challenges and Limitations
9.5 Recent Advancements
References

Chapter 10: DART-MS Applications in Pharmaceuticals

10.1 Pharmaceutical Analysis
10.2 Quality Assurance
10.3 Illegal Active Pharmaceutical Ingredients and Counterfeit Drugs
10.4 Drug Development
References

Chapter 11: Application of DART-MS in Natural Phytochemical Research

11.1 Introduction
11.2 Direct Analysis in Real Time (DART) Mass Spectrometry
11.3 DART-MS Parameter Optimization for Phytochemical Analysis
11.4 Applications of DART-MS in Phytochemical Research
11.5 Hyphenated DART-MS Techniques for Phytochemical Analysis
11.6 Improving Sensitivity of DART-MS for Phytochemical Analysis
11.7 DART -MS as Process Analytical Technology
11.8 Future Perspective
References

Chapter 12: Miscellaneous Applications of DART-MS

12.1 Introduction
12.2 Usefulness of Negative-Ion Mode
12.3 Application to Archeology and Conservation
12.4 Application by Using TLC
12.5 Application to Low Volatility, Chemical Warfare, and Homeland Security
12.6 Pheromone Profiles from Live Animals in Parallel with Behavior
12.7 Application to Distinction of Plants with Similarity
12.8 Application to Space
12.9 Application to Bituminous Coals
12.10 Application to Detection of Nicotine
12.11 Other Potential Applications of DART-MS
Acknowledgment
References

Chapter 13: Inherent Limitations and Prospects of DART-MS

13.1 Aspects of Inherent Limitations of DART-MS
13.2 DART versus Other Ambient Ion Sources
13.3 Prospects of DART-MS
13.4 Concluding Remarks
References

Index

End User License Agreement

List of Illustrations

Chapter 1: Introduction of Mass Spectrometry and Ambient Ionization Techniques

Figure 1.1 Portrait of Antoine-Laurent Lavoisier and his wife by Jacques-Louis David, about 1788.
Figure 1.2 Photograph of Robert Bunsen (right) and Gustav Kirchhoff (left).
Figure 1.3 Wilhelm Ostwald (1853–1932). Recipient of the 1909 Nobel Prize for Chemistry “in recognition of his work on catalysis and for his investigations into the fundamental principles governing chemical equilibria and rates of reaction.”
Figure 1.4 Essence and elemental relationships of contemporary analytical chemistry.
Figure 1.5 Schematic representation of the parabola mass spectrograph. A, the gas inlet; B, the anode; C, the discharge tube; D, the port to the vacuum system; E, the cathode; F, the magnetic shields; G, the water jacket for cooling; H, the insulators; and J, the photographic plate used to detect the ions.
Figure 1.6 Schematic representation of Dempster's direction-focusing mass spectrometer that includes E, the ion-detection device; G, the glass ion-source housing containing the filament F that was heated to produce electrons that bombarded the platinum sample holder P; and B, the analyzer section surrounded by the magnet. A potential difference between the sample holder and the first slit (S₁) provided the ion acceleration and collecting with intermediate slit (S₂) and collector slit (S₃).
Figure 1.7 Schematic view of the quadrupole mass spectrometer or mass filter.
Figure 1.8 First FT-ICR mass spectrum.
Figure 1.9 Overview of the workflow of MS for human proteome map drafting. (a) The adult/fetal tissues and hematopoietic cell types that were analyzed to generate a draft map of the normal human proteome. (b) The samples were fractionated, digested, and analyzed on the high-resolution and high-accuracy Orbitrap mass analyzer.
Figure 1.10 A schematic view of a mass spectrometer.
Figure 1.11 A schematic view of an electron ionization mechanism.
Figure 1.12 A schematic view of atmospheric pressure chemical ionization mechanism.
Figure 1.13 A schematic view of fast atom bombardment ionization mechanism.
Figure 1.14 A schematic view of the direct exposure ionization method for DEI or DCI.
Figure 1.15 A schematic view of electrospray ionization mechanism.
Figure 1.16 A schematic view of matrix assisted laser desorption/ionization mechanism.
Figure 1.17 A schematic view of field desorption or field ionization.
Figure 1.18 A schematic view of inductively coupled plasma torch.
Figure 1.19 A schematic view of low-temperature plasma ionization for mass spectrometry.
Figure 1.20 A pattern of flowers to summarize ambient ionization techniques.
Figure 1.21 Cutaway view of the DART Ref. [112]. ©The American Chemical Society, 2005.
Figure 1.22 Main reactions of DART ionization mechanism.

Chapter 2: DART Mass Spectrometry: Principle and Ionization Facilities

Figure 2.1 Schematic representation of a DART source mounted in front of the atmospheric pressure interface (API) of a mass spectrometer.
Figure 2.2 Diagram of possible reactions generating the positive ion background from ambient air in DART ionization.
Figure 2.3 Positive ion background spectra for (a) an APCI source with 0.5 mm corona discharge needle distance to orifice, (b) DART ionization conditions when the ion source is positioned close to the entrance orifice of the API mass spectrometer (∼3 mm) and the gird electrode potential is increased from +250 to 650 V, (c) a typical APCI source acing in thermal and equilibrium conditions with 0.5 mm corona discharge needle distance to orifice, and (d) typical DART ionization conditions. For the APCI source, nitrogen is used as the carrier and nebulizing gas whereas in DART-MS, helium is the Penning ionization gas.
Figure 2.4 Example of a thermodynamic cycle used for successively evaluating the proton affinities PA(S)_n+1 of the solvent dimer (n = 1) and trimer (n = 2). In this illustration, $c02-math-012$ is the standard molar enthalpy change in the steps of the cluster formation, that is, for a reaction with n = 0–1 and then with n = 1–2, PA(S_n) is the proton affinity of the corresponding neutral containing n solvent molecules.
Figure 2.5 Positive DART mass spectrum of (a) l-Lysine (Lys) and (b) Glycin (Gly).
Figure 2.6 Positive ion DART mass spectrum of dye textiles such as alizarin.
Figure 2.7 Comparison of positive ion DART mass spectra of extra virgin olive oil (a) without and (b) with the presence of ammonia vapors. The region of the displayed mass spectra (m/z 820–910) shows the presence of triacylglycerols (TAGs) as [M+H]⁺ quasi-molecular ion in (a) and [M+NH₄]⁺ adducts in (b). Note that (*) is triolein (C₅₇H₁₀₄O₆, MW 884.78) and (**) is palmityldiolein (C₅₅H₁₀₂O₆, MW 858.77).
Figure 2.8 DART mass spectra directly obtained from gaseous effluent of gas chromatography at the time corresponding to the elution of methyl dodecanoate under conditions corresponding to (a) a 3 mm DART/orifice spacing and a 650 V grid potential for producing ion background of Figure 2.3b and (b) a 15 mm DART/orifice spacing and a 250 V grid potential for producing protonated reactants ions as in Figure 2.3d.
Figure 2.9 DART mass spectra of n-hexadecane obtained in chemical equilibrium conditions of the source, that is, with a grid electrode at 250 V, positioned far from the orifice and for a heater temperature of (a) 200 °C and (b) 300 °C.
Figure 2.10 DART mass spectra of hexadecane obtained in conditions where the O₂⁺ ion is present for charge exchange reaction with the grid voltage at (a) 50 V, (b) 350 V, and (c) 650 V.
Figure 2.11 Thermodynamic cycle used to evaluate the PA value of the radical [S−H]^•.
Figure 2.12 Graph representing the PA(S_n) − PA([S−H]^•) values for different solvent molecules and their dimers, as a function of the PA(S_n) − PA(H₂O) values where n = 1 or 2 (data from Table 2.5). The PA values (in bold) and chemical formulae of the solvents are positioned closer to the markers (black diamond) of the data of the Table 2.5.
Figure 2.13 Positive ion DART mass spectrum of methanol.
Figure 2.14 Positive ion DART mass spectrum of toluene.
Figure 2.15 Diagram of possible reactions generating the negative ion background from ambient air in DART ionization.
Figure 2.16 Negative ion background DART mass spectra obtained in standard conditions and proposed by Cody and coworkers in Refs [1] (a) and [40] (b).
Figure 2.17 DART-MS spectra of a lichen metabolite such as stictic acid, in negative ion mode (a) and positive ion mode (b).
Figure 2.18 Negative ion DART mass spectrum of hemoventosin (a lichen metabolite) illustrating the formation of a radical anion and deprotonated molecule.
Figure 2.19 Positive DART mass spectra obtained using (a) helium and (b) argon in the gas stream. Protonated molecule and dimer of the sample are noted as [M+H]⁺ and [2M+H]⁺; fragment ions noted as [I+H]⁺ and [C+H]⁺ correspond to the dissociation of the bond between the cytidine and the sugar.
Figure 2.20 Negative DART mass spectra obtained by using (a) helium and (b) argon in the gas stream. The deprotonated molecule [M−H]⁻ of glucose is detected at m/z 179, whereas the fragment ion at m/z 161 results from a water loss.
Figure 2.21 Time-dependence of ln(SY) at different actual temperatures of the helium stream of the DART source, with SY values.
Figure 2.22 Mycosporine serinol and the m/z values of its protonated molecule and its dehydrated form.
Figure 2.23 Positive DART mass spectra of protonated lichen metabolite (atranorin) at increasing orifice 1 voltage values (A = 5 V, B = 15 V, C = 25 V, and D = 45 V).

Chapter 3: Sampling and Analyte Enrichment Strategies for DART-MS

Figure 3.1 Screening process of synthetic antidiabetic drug adulteration in herbal supplement. Reprinted from Ref. [23]. Copyright © 2011, with permission from Royal Society of Chemistry.
Figure 3.2 Coupling of SBSE with DART-MS. Reprinted from Ref. [38]. Copyright © 2015, with permission from Elsevier.
Figure 3.3 Schematic of the online coupling of IT-SPME with DART. Reprinted from Ref. [47]. Copyright © 2014, with permission from American Society of Chemistry.
Figure 3.4 Schematic of the MRCC-DART-MS system. Reprinted from Ref. [52]. Copyright © 2014, with permission from Elsevier.

Chapter 4: Optimization of DART and Mass Spectrometric Parameters

Figure 4.1 The representative mass spectra of the extracts of mulberry leaves monitored by DART-MS in positive ion mode.
Figure 4.2 Helium gas flow rate effect on DART-TOF-MS sensitivity for metabolomic analysis of derivatized serum. (a) Mass spectra obtained at various helium flow rates, (b) number of metabolites found by matching to HMDB database at different helium flow rates, and (c) observed S/N of mass spectrometric signals at m/z 205.12, 467.22, and 762.25.
Figure 4.3 Effect of helium gas temperature on DART-TOF-MS sensitivity for metabolomic profiling of derivatized serum: (a) background corrected mass spectra at various helium temperatures, (b) number of metabolites matched to HMDB database, and (c) change in S/N of three mass spectrometric signals at m/z 205.12, 467.22, and 762.25 versus helium temperature.
Figure 4.4 Scheme for manual positioning of the HPTLC (high performance thin layer chromatography) plate into the DART gas beam; response was best at a distance of approximately 1 mm aside orifice 1 and an angle of about 160° vertical to the gas flow.
Figure 4.5 The mass spectra of the DNJ standard solution monitored by DART-MS in positive ion mode (a) and negative ion mode (b).

Chapter 5: Interfacing DART to Extend Analytical Capabilities

Figure 5.1 Schematic diagram for the coupling of TLC with DART-MS. (Reprinted from Ref. [9]. Copyright © 2007, with permission from Elsevier), showing the manual positioning of HPTLC plate into the DART ionization region.
Figure 5.2 Photo of the DART SVP-A source, allowing “desorption at an angle,” enabling horizontal and vertical position adjustment and ionizing samples from an angle.
Figure 5.3 Photo of the further developed TLC-DART-MS interface using an x–y–z stage for better surface scanning.
Figure 5.4 Schematic diagram of the HPLC-DART-MS interface developed by Eberherr et al. The sample solution flowing out from the HPLC was led into a stainless steel or fused silica capillary (3) via a PEEK capillary (1) and a zero dead volume junction (2). Then the sample solution would form a liquid jet (5). It was placed between the DART outlet (4, the insulator cap with grid electrode at the He outlet of the DART source) and the MS inlet (6), thus it could be ionized. (7) represents the groove for fraction collection.
Figure 5.5 Schematic drawing of the HPLC-DART-MS interface developed by Beissmann et al. Make-up solution (2) was added in this interface. The other parts were similar to those in Figure 5.4, including the PEEK capillary from HPLC delivering separated samples (1), T-junction (3) connecting 1, 2, and 4, fused silica capillary (4), DART outlet (5), liquid jet (6), MS inlet (7) and the groove for fraction collection (8).
Figure 5.6 Scheme for the interface coupling HPLC with DART-MS used by Chang et al. The sample solution was first detected by a UV detector (1), then transferred by a PEEK tube (2) to a PEEK T-junction (3). The solution was split in the T-junction, the excess sample was collected in 4, and the rest was led to a fused silica capillary (6) by a PEEK junction (5).
Figure 5.7 Photo of the spray DART for analyzing liquid samples using DART-MS. A spray needle was used for nebulizing the sample solutions, thus they could be ionized by DART.
Figure 5.8 Schematic diagram of the CE-DART-MS interface developed by Chang et al. A three-layer coaxial spray tip originally designed for CE-ESI-MS was used. The innermost layer was used for inserting the CE capillary, and the other two layers were used for the sheath liquid and the nebulizing gas. The CE solutions was blended with the sheath liquid, and then nebulized and ionized, and finally analyzed by MS.
Figure 5.9 (a) Relative MS signals of 4-aminoantipyrine (100 µg mL⁻¹) in various buffers: (A) water; (B) 15 mM sodium borate; (C) 30 mM sodium borate; (D) 50 mM sodium borate; (E) 100 mM sodium borate; (F) 15 mM SDS in 15 mM sodium borate; (G) 30 mM SDS in 30 mM sodium borate; (b) mass spectrum of analytes dissolved in pure water; (c) mass spectrum of analytes dissolved in 15 mM sodium borate buffer containing 15 mM SDS.
Figure 5.10 Schematic diagram of the SPR-DART-MS interface. A two-later coaxial spray tip originally used for LC-ESI-MS was employed. The SPR sample flow was connected to the inner layer of the spray tip, and the nebulizing gas was connected to the outer layer. The samples could first be analyzed by SPR, then nebulized and ionized in the interface, and finally analyzed by MS.
Figure 5.11 Relative intensities of the quasi-molecular ions of each analyte dissolved in different buffers using the designed interface. For each analyte, the intensity obtained from its extracted ion chromatogram was normalized using the intensity achieved from the water matrix (n = 3). Extracted ions: acetaminophen (m/z = 152, [M+H]⁺); metronidazole (m/z = 172, [M+H]⁺); and quinine (m/z = 325, [M+H]⁺) and (m/z = 178, [M−H]⁻).
Figure 5.12 Schematic diagram of the coupling of DART with DTIMS. The interface included the drift tube (i), entrance tube (ii), entrance electrode (iii), sampling tube (iv) and the DART source (v) on an adjustable rail (vi). The inset (vii) shows the front of the instrument.
Figure 5.13 Schematic of the interface coupling DART with IMS developed by Keelor et al. Turning on the potential on the repeler point electrode could significantly enhance the detected signals.

Chapter 6: Application of DART-MS in Foods and Agro-Products Analysis

Figure 6.1 Measured masses of highly hazardous pesticides obtained by DART-MS (1000 mg L⁻¹). The insets show the experimental isotope patterns of the identified ions. The [M]⁺·ions in the positive were labeled (⋆). (a) Carbofuran, (b) Phorate, (c) Ethoprophos, and (d) Fipronil.
Figure 6.2 (a) DART-MS mass spectrum of 70% acetamiprid WDG spiked with phorate and ethoprophos in the positive mode. (b) DART-MS mass spectrum of 70% acetamiprid WDG spiked with fipronil in the negative mode.
Figure 6.3 DART-MS spectra of caffeine standard solution 10 mg L⁻¹ in positive ion mode.
Figure 6.4 Typical DART-MS spectra obtained from green tea beverage (a), soft drink (b), tea (c), and instant coffee (d). The [M+H]⁺ and [2M+H]⁺ ions of caffeine are marked with (•)and (⋆).

Chapter 7: Application of DART-MS for Industrial Chemical Analysis

Figure 7.1 Partial positive ion DART spectrum of baking mold at 300 °C with the mass differences annotated between adjacent peaks (a); the values are close to the theoretical Δm/z = 74.018791 of OSi(CH₃)₂. The correct PDMS ionic formulas are marked in the list (b). The isotopic pattern of the signal at m/z 832.23886 is compared to the theoretical pattern (c).
Figure 7.2 DART-FT-ICR spectrum of an NUK Happy Days pacifier reveals the release of some low-mass polyethylene glycols (PEGs) that are detected as [PEG + NH₄]⁺ ions in the molecular weight range of 300–600 u. Silicones are observed starting from m/z 610.
Figure 7.3 Mass spectrum obtained using negative ion detection with the DART AccuTOF mass spectrometer of the sample labeled “China Drywall.”
Figure 7.4 Coupling of the stir-bar sorbent extraction (SBSE) with the DART LTQ-Orbitrap mass analyzer.
Figure 7.5 Total ion current (TIC) (a) and extracted ion chromatogram (EIC) corresponding to (b) TnBP (m/z = 267.17–267.18) and (c) d-TnBP (m/z = 294.34–294.35) observed when combining Twister™ extraction with DART-LTQ Orbitrap analysis. (d) displays the DART-MS spectrum of TnBP and d-TnBP at the 100 mg L⁻¹ level and (e) the calibration curve in water spanning 10–750 g L⁻¹.
Figure 7.6 Positive ion DART spectra of shortbread undersurfaces after baking. (a) Spectrum of the blank sample in the m/z 700–1900 range, (b) expanded view of m/z 450–1100 showing the TAG ions in detail and (c–e) further expanded to m/z 1195–1220. Spectrum (c) is taken from the blank shown in (a). Spectra (d) and (e) are obtained after baking on 2_Toppits and 3_Selection, respectively. The specific mass defects of TAG and PDMS enable good separation of peaks because of PDMS ions from those by TAGs (marked with arrows).
Figure 7.7 The mass spectra of the DNJ standard solution monitored by DART-MS in positive ion mode (a) and negative ion mode (b).
Figure 7.8 The representative mass spectra of the extracts of mulberry leaves monitored by DART-MS in positive ion mode.
Figure 7.9 Comparison of the tolerance of complex matrix between ESI- and DART-MS in the detection of glucocorticoids (20 µg mL⁻¹): (a) ESI-MS analysis of acetonitrile dissolved standard mixture, (b) ESI-MS analysis of essential oil dissolved standard mixture, (c) DART analysis of acetonitrile dissolved standard mixture, (d) DART analysis of essential oil dissolved standard mixture.
Figure 7.10 The DART-CID-MS/MS spectra and the proposed ion fragmentation mechanism of PN.
Figure 7.11 DART mass spectra of Bic Round Stic black ballpoint ink 4 and 332 days after being written.
Figure 7.12 Relative intensities of peaks in the DART mass spectrum of Bic Round Stic blank ballpoint ink as it ages after being written.
Figure 7.13 The DART mass spectra of 1-allyl-3-methylimidazolium chloride, [AMIM][Cl]: IL 1, with (a) positive ion and (b) negative ion mode analysis. Insets show [C₂A]⁺ and [C₂A₃]⁻ ion cluster isotopic patterns and CID mass spectra, respectively.
Figure 7.14 The DART mass spectra of trihexyltetradecylphosphonium bis(trifluoromethylsulfonyl)imide, [THTDP][NTf₂], using (a) positive ion and (b) negative ion mode analysis.

Chapter 8: Application of Direct Analysis in Real Time Coupled to Mass Spectrometry (DART-MS) for the Analysis of Environmental Contaminants

Figure 8.1 Transmission module configured for the desorption ionization of analytes.
Figure 8.2 Experimental protocol and configuration of the online IT-SPME-DART-MS system. The entire experimental procedure involved four parts: (a) activation, (b) sampling, (c) washing, and (d) online desorption and detection (top view, where d₁ = d₂ = 3 mm).
Figure 8.3 Quantification using DART-TOF-MS showing single ion current of m/z 297.05–207.06 (imazalil [M+H]⁺ value extracted with a mass window of 10 mDa) (1–2500 ng) and working curve of imazalil (a) for standard solutions of imazalil in methanol and (b) standards spiked in an apple peel.
Figure 8.4 Coupling the Stir Bar Sorbent Extraction (SBSE) with the direct analysis in real-time linear triple quadrupole (DART-LTQ) Orbitrap mass analyzer.
Figure 8.5 (a) Total ion current (TIC; 1) and extracted ion current (EIC; 2, 3) corresponding to TBP (m/z = 267.17–267.18) and d-TBP (m/z = 294.34–294.35) observed when employing Twister™ extraction combined with DART-LTQ Orbitrap. 4) displays the DART/MS spectrum of TnBP and d-TnBP at the 100 mg L⁻¹ level and (5) the calibration curve in water spanning 10–750 g L⁻¹. All Figure in row (b) correspond to DBP and d-DBP.
Figure 8.6 Atomic and molecular Br signal intensity with varying gas temperature.
Figure 8.7 TIC and extracted ion chromatograms for a set of four parabens at a concentration level of 0.4 mg mL⁻¹. Peak assignment: (1), methyl paraben; (2), ethyl paraben; (3), propyl paraben; (4), butyl paraben.
Figure 8.8 (a) DART (+) MS spectrum and (b) Van Krevelen diagram for n-dodecane SOA produced under low-NO conditions with ammonium sulfate seed aerosol.

Chapter 9: Application of DART-MS in Clinical and Pharmacological Analysis

Figure 9.1 Phenotypic features of the dorsal skin of mice. (a) At 1 week, UVB irradiation and topical treatment with RP in dorsal skin of mice. (b) At 2 weeks, only topical treatment with RP in the dorsal skin of mice.
Figure 9.2 Representative DART-MS spectra in the positive ion mode. (a) UV− group, (b) UV+ group, (c) UV + RP group.
Figure 9.3 PCA score plot (a) and loading plot (b) by DART-MS spectral data in the positive ion mode. Symbols representation: squares, UV−; circles, UV+; diamonds, UV + RP.
Figure 9.4 Microscopic images of a dried, derivatized human serum sample (a) before and (b) after TM-DART analysis with the (c) corresponding background-corrected positive ion mode mass spectrum in the m/z 50–850 range. The inset details the signals observed upon zooming into the baseline.
Figure 9.5 Schematic diagram of the confined DART ion source for breath analysis. A breath collector was used to introduce the exhaled breath to the ion source for analysis.
Figure 9.6 Mass spectrum of the exhaled breath of a healthy male volunteer obtained by cDART in the positive mode. The spectrum was obtained by averaging over a single breath (about 5 s).
Figure 9.7 Real-time ion intensity variations of TIC and 11 ions as a function of time. In the figure, an increase in ion intensity corresponds to each breathing cycle. In the experiments, the exhaled breath was analyzed every 30 s, and every exhalation lasted about 4 s. The first 2 min correspond to normal breath, and the lozenge was swallowed at 36 min (indicated by the dotted line). The ion intensity variations after 36 min correspond to the concentration variations of the volatile compounds in mouth with time after drug usage.
Figure 9.8 Matrix effect of DART for analysis of verapamil in samples by varying water content.

Chapter 10: DART-MS Applications in Pharmaceuticals

Figure 10.1 Linear discriminant analysis plot of codeine isomers.
Figure 10.2 Comparison of positive-ion mode DART-HRTOF-MS spectra under in-source CID conditions of the World Seed Supply Kanna 25X product versus an ephedrine standard, rendered as a head-to-tail plot. The top spectrum is that of the Kanna product and the bottom spectrum, that of the ephedrine standard. The protonated parent (nominal m/z 166) and fragment ions (nominal m/z 148, 133, 115, 105, 91, 70, 56) are found in both the Kanna product and the ephedrine standard.
Figure 10.3 Analyses of formulation 4 by (a) 2D DOSY ¹H NMR in DMSO-d₆, with TMPS as internal reference standard, (b) DART-MS in positive-ion mode, and (c) DESI-MS in positive-ion mode.
Figure 10.4 Representative total diode array chromatograms for the reaction monitoring of an indole converting to an N-methylindole via LC/UV/ESI-MS: UV spectra at (a) 0 min, (b) 20 min, (c) 40 min, (d) 80 min, (e) 140 min, and (f) 16 h; (mass spectral data for the indole, [M+H]⁺) 254, and (N-methylindole, [M+H]⁺) 268, generated via DART/MS (350 °C) at (g) 0 min, (h) 20 min, (i) 40 min, (j) 80 min, (k) 140 min, and (l) 16 h.

Chapter 11: Application of DART-MS in Natural Phytochemical Research

Figure 11.1 Positive-ion mode HR-DART-TOF mass spectra of a leaf clipping and an ethanol extract of the leaf of Mitragyna speciosa, rendered as a head-to-tail plot. Although the spectra show a large number of peaks in common, including those corresponding to major alkaloids, many more peaks representing individual leaf constituents are observed in the spectrum of the leaf, as opposed to that of the extract.
Figure 11.2 DART mass spectrum of Piper betle leaf of the variety Saufia.
Figure 11.3 DART mass spectra of leaves of male and female Piper betle.
Figure 11.4 Percentage of ionization of compounds in Piper species.
Figure 11.5 Comparative DART-MS fingerprint spectra of roots of Rauwolfia species.
Figure 11.6 DART mass spectra of B. petiolaris fruit, leaf, stem, and root.
Figure 11.7 DART-MS based strategy for analysis of Berberis aristata.
Figure 11.8 Multivariate PCA plot to discriminate the substituents of Berberis aristata.
Figure 11.9 TLC chromatogram of an extract of turmeric and DART spectra from three major bands of curcuminoids. TLC plate was visualized under irradiation with UV light (365 nm).

Chapter 12: Miscellaneous Applications of DART-MS

Figure 12.1 Representative mass spectra of MNG, DNG, TNG, EGDN, PGDN, RDX, tetryl, HMX, and PETN. All readily form the chloride adduct [13].
Figure 12.2 DART-MS of counterfeit.
Figure 12.3 DART-MS of examples of pills and medicines.
Figure 12.4 DART-MS of tomato skin.
Figure 12.5 DART-MS of pepper.
Figure 12.6 DART-MS of flesh, seed, and membrane part.
Figure 12.7 DART-MS of chopped chives.
Figure 12.8 DART-MS of orange peel.
Figure 12.9 DART-MS of shirt stain.
Figure 12.10 DART-MS of (a) TAPT and (b) HMTD.
Figure 12.11 DART-MS of nitroglycerin on tie.
Figure 12.12 DART-MS of black rubber.

Chapter 13: Inherent Limitations and Prospects of DART-MS

Figure 13.1 Hair analysis with the DART transmission module mounted on an Exactive Orbitrap system (a). Helium temperature optimization for delta-9 tetrahydrocannabinol (THC) signal intensity (m/z 315.2319) applied on stainless steel mesh sheet (b) and blank hair (c).
Figure 13.2 Extended mass range: DART-MS spectrum (Apex-Qe FT-ICR mass spectrometer, Bruker Daltonik, Bremen, Germany) of ionic liquid 1-butyl-3-methylimidazolium (C⁺) tricyanomethanide (A⁻) high-mass cluster ions in positive-ionization mode (a). Detailed section of the same spectrum with focus on the eight highest mass cluster ions with Δm/z values corresponding to the mass of CA (calculated 229.1327 u): highest m/z 6786.8924 of cluster [C₃₀A₂₉]⁺ (b). Zoom: isotopic pattern of the cluster ions [C₂₆A₂₅]⁺ and [C₂₇A₂₆]⁺ (c).
Figure 13.3 Illustration of the stir bar sorbent extraction (SBSE) application in combination with DART LTQ-Orbitrap MS.
Figure 13.4 Influence on signal intensity using a dopant: extra virgin olive oil dilutions in toluene (1 : 50, V/V) analyzed by DART-TOFMS without dopant (a) and with dopant (b).
Figure 13.5 Modified OpenSpot sampling card (a) with SPMESH preconcentration material, produced by dipping the mesh into a sol–gel solution. FESEM image of the cross-sectional view on the PDMS-coated wire.
Figure 13.6 Quantitative HPTLC surface scanning. Visualization of the scan track along butyl 4-hydroxybenzoate (BE) zones of 600 ng/band at 254 nm showing the intense zones and slightly the scan track (a) and at 366 nm showing slightly the zones due to thermal activation and an intense scan track with the left-aligned warm-up position (b). TIC and EIC of the scan with high signal intensities and %RSD of 4% (n = 5) for the EIC (c). Mass spectra of BE with deprotonated molecule, oxidation product, and dimer (d).
Figure 13.7 Comparison of the independent EIC signals obtained by DART-MS and densitometric signals at a wavelength of 254 nm (a) of four separated but adjacent parabens (b, each 120 ng/band). Decreasing desorption and ionization rate and thus decreasing EIC signal intensities correlated with the increasing molecular weight.
Figure 13.8 Illustration of the DART-based laser ablation technique PAMLDI for MS imaging at a pixel size of 60 × 60 µm.

List of Tables

Chapter 1: Introduction of Mass Spectrometry and Ambient Ionization Techniques

Table 1.1 Historical developments in mass spectrometry
Table 1.2 Ambient ionization (AI) techniques and analytical traits
Table 1.3 IE and ME of carrier gases and IE of main reaction intermediates
Table 1.4 Multiple assorted devices of DART

Chapter 2: DART Mass Spectrometry: Principle and Ionization Facilities

Table 2.1 Ionization energies (IE), internal energies (E_int), and nature of excited states of gas mainly used in DART ionization
Table 2.2 Chemical parameters of the reactions depicted in Figure 2.2
Table 2.3 Proton affinities (PA) and boiling points of solvents available in DART ionization
Table 2.4 Proton affinities (PA) of the dimer and trimer of solvents available in DART ionization^a
Table 2.5 Thermodynamic data such as bond enthalpies (D_298K) and ionization energies (IE) leading to the evaluation of the proton affinities (PA) of the radical [S−H]^• (see the values in the fifth column)
Table 2.6 Ionization energy (IE) proton affinity (PA) and relative ion intensity of radical cations and protonated molecules measured in DART analysis using methanol, toluene, or hexane as sampling solvent
Table 2.7 Chemical parameters of the reactions depicted in Figure 2.15

Chapter 4: Optimization of DART and Mass Spectrometric Parameters

Table 4.1 The candidate reagent used for DART ion source

Chapter 6: Application of DART-MS in Foods and Agro-Products Analysis

Table 6.1 Multireaction monitoring (MRM) transitions and MS operating parameters selected for the analysis of 18 organophosphate pesticides
Table 6.2 Maximum permitted tolerances for relative ion intensities using a range of mass spectrometric techniques
Table 6.3 Relative intensities and relative deviations of studied pesticides in DART-MS mass spectrum (n = 5)
Table 6.4 Limits of detection (LOD) and maximum residue limits (MRLs).
Table 6.5 Validation of detection capability of the DART-MS method for fortified pesticide residues in cherry tomato (n = 3)
Table 6.6 Selected performance characteristics of DART-MS applied to surface swabbing technique.
Table 6.7 Relative intensities and relative deviations of studied pesticides in DART-MS mass spectrum (n = 5)
Table 6.8 Limits of detection (LOD) and maximum residue limits (MRLs)
Table 6.9 Physico-chemical properties of highly hazardous pesticides
Table 6.10 Relative intensities and relative standard deviations (RSDs) of isotope peaks observed in DART-MS mass spectrum of studied highly hazardous pesticides in agrochemicals (n = 5)
Table 6.11 Comparison of DART-MS with other methods for the detection of caffeine in various samples

Chapter 7: Application of DART-MS for Industrial Chemical Analysis

Table 7.1 Quantification of PDMS release
Table 7.2 Signal-to-noise data from each sample for DEG and EG in unspiked, 0.1%, and triplicate 0.2% spiked preparations

Chapter 8: Application of Direct Analysis in Real Time Coupled to Mass Spectrometry (DART-MS) for the Analysis of Environmental Contaminants

Table 8.1 Applications of direct analysis in real time (DART) coupled to mass spectrometry (MS) for environmental contaminants analysis

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I dedicate this book to my beloved parents, Yuante Tung and Shuchen Hsu.
I am best endowed with your love, goodness, honesty, wisdom, endeavors, and perseverance; for that, thank you so much.

Preface

All the authors who have contributed to this book have tried to describe that direct analysis in real time (DART), as a representative ambient ionization technique initiated by Penning ionization of atmosphere or electron emission from surfaces, has developed into a potential analytical tool from a mechanistic perspective for various applications.

In Chapter 1, the evolution of mass spectrometry and its role in contemporary analytical chemistry have been reviewed, desorption/ionization in mass spectrometry is discussed, and ambient ionization and DART are briefly introduced. In Chapter 2, the principle of DART and ionization mechanisms are well depicted.

In Chapter 3, to overcome DART limitations in terms of sample uniformity, ionization energy and efficiency, sample preparation and analyte-enrichment strategies are provided. In Chapter 4, parameters that influence DART-MS performance are summarized to optimize and quantitate analytes with improved sensitivity and accuracy. To further extend analytical capabilities, interfacing TLC, GC, HPLC, CE, SPR, and IMS with DART-MS has been realized and summarized in Chapter 5 systematically.

Abundant DART-MS applications for foods/agro-products, industrial chemicals, environmental contaminants, pharmaceuticals, clinical/pharmacological analysis, natural phytochemical research, and relevant DART-MS reports are comprehensively presented in Chapters 6–12, respectively. In Chapter 13, inherent limitations of DART-MS are thoroughly investigated. In addition, comparisons for DART with other ambient ion sources are made. Furthermore, some prospective applications, such as DART with high resolution MS, instrumental automation and miniaturization, surface scanning and imaging, and so on, are rather promising and encouraging.

I hope both analytical experts and novice investigators will find this book very useful, and acknowledge all the authors who have contributed to this book with great appreciation thereof.

Yiyang Dong

Oct 8th, 2017
Beijing University of Chemical Technology
China

About the Editor

Yiyang Dong obtained his bachelor's degree in Chemistry in 1989 from the East China Normal University where he acquired knowledge in fundamental analytical chemistry and mass spectrometry; then he went on to pursue his postgraduate study at the Nankai University and got his master's degree in liquid chromatography. In 1995, he went to the Peking University to investigate capillary electrophoresis for chiral separation and obtained a doctorate of philosophy in separation science in 1998. He also carried out postdoctoral research at Prof. Kitamori's laboratory in the University of Tokyo, Japan, to study microfluidics and related miniaturized bioanalytical techniques and tried to hyphenate these frontier techniques with mass spectrometry (MS) for various analytical applications later.

In early 2012, Dong joined the Beijing University of Chemical Technology (BUCT) as a full professor of Chemistry through a talent program and set up a research laboratory for food safety analysis and risk assessment, where he developed mass spectrometric and several facile bioanalytical methodologies for fast identification of small molecular adulterants, additives, and functional ingredients in various food matrices. It was here that his interest in direct analysis in real time (DART) and other ambient ionization strategies began with a cooperatively gelivable investigator Professor Wei Yong from the Chinese Academy of Inspection and Quarantine (CAIQ).

This research interest continued when Dong's graduate students Tianyang Guo and Pingping Fang began to participate in relevant DART research projects. Recent years have witnessed a broad utilization of DART in various research fields to introduce DART with representative analytical applications; he is therefore pleased to be the editor of this book on MS and feels happy to share with the audience the state of the art.

Direct Analysis in Real Time Mass Spectrometry

Principles and Practices of DART-MS

Preface

About the Editor