Time-Resolved Mass Spectrometry From Concept to Applications

Time is an important factor in physical and natural sciences. It characterizes the progress of chemical and biochemical processes. Mass spectrometry provides the means to study molecular structures by detecting gas-phase ions with the unique mass-to-charge ratios. Time-resolved mass spectrometry (TRMS) allows one to differentiate between chemical states that can be observed sequentially at different time points. Real-time mass spectrometric monitoring enables recording data continuously with a specified temporal resolution. The TRMS approaches – introduced during the past few decades – have shown temporal resolutions ranging from hours down to microseconds and beyond.
This text covers the key aspects of TRMS. It introduces ion sources, mass analyzers, and interfaces utilized in time-resolved measurements; discusses the influence of data acquisition and treatment; finally, it reviews most prominent applications of TRMS – in the studies of reaction kinetics and mechanism, physicochemical phenomena, protein structure dynamics, biocatalysis, and metabolic profiling.
It will assist science and engineering students to gain a basic understanding of the TRMS concept, and to recognize its usefulness. In addition, it may benefit scientists who conduct molecular studies in the areas of chemistry, physics and biology.

Pawel Urban is an Assistant Professor in the Department of Applied Chemistry at National Chiao Tung University, Taiwan. He studied his MISMaP MSc, in biology at the University of Warsaw, Poland between 1999 & 2002. He then studied at the University of York UK, between 2004 & 2007 where he gained his PhD, in Chemistry. He began working as a postdoctoral Assistant in the Faculty of Biology, University of Warsaw, before moving to Swiss Federal Institute of Technology (ETH), Zurich and 2 years later to National Chiao Tung University, where in both institutes he?worked as a PDRA, before beginning his current role of Assistant Professor.

Yu-Chie Chen is a Professor of Chemistry in the Department of Applied Chemistry, National Chiao Tung University, Taiwan. She obtained her Bachelor degree at Kung University, Taiwan, her Masters at Sun Yat-sen, Taiwan and her P.h.D at Montana State University, USA. Before working at National Chiao Tung University, she held positions at Swiss Federal Institute of Technology Zurich, Tzu Chi Medical and Tzu Chi University.

Yi-Sheng Wang is an Associate Research Fellow at the Genomics Research Center, Academia Sinica, Taiwan. He acheived his Chemistry Ph.D. at the National Taiwan University, in 2001. Between 2001 & 2005, he began working as a?Postdoctoral Fellow, at the Institute of Atomic and Molecular Sciences (IAMS), Academia Sinica, (including a Postdoctoral Fellow at?National High Magnetic Field Laboratory (NHMFL), Florida State University, U.S.A. between 2002-2003). In 2005, he moved to the Genomics Research Center, Academia Sinica, Taiwan, as a Assistant Research?Fellow, until 2011, when he was promoted to?his current position of Associate Research Fellow.

Author Biographies xi

Preface xiii

Acknowledgments xv

List of Acronyms xvii

1. Introduction 1

1.1 Time in Chemistry 1

1.2 Mass Spectrometry 3

1.3 Time-resolved Mass Spectrometry 5

1.4 Dynamic Matrices 6

1.5 Real-time vs. Single-point Measurements 6

1.6 Further Reading 7

References 7

2. Ion Sources for Time-resolved Mass Spectrometry 11

2.1 Electron Ionization 12

2.2 Chemical Ionization 14

2.3 Atmospheric Pressure Chemical Ionization 18

2.4 Electrospray Ionization 19

2.5 Atmospheric Pressure Photoionization 24

2.6 Desorption/Ionization 25

2.6.1 Fast Atom Bombardment 26

2.6.2 Laser Desorption/Ionization 27

2.7 Innovations in the 21st Century 33

2.7.1 Ion Sources Derived from Electrospray Ionization 34

2.7.2 New Ion Sources Derived from Laser Desorption/Ionization 39

2.7.3 Plasma-based Ion Sources 40

2.8 Concluding Remarks 43

References 43

3. Mass Analyzers for Time-resolved Mass Spectrometry 53

3.1 Overview 53

3.2 Individual Mass Analyzers 54

3.2.1 Time-of-flight Mass Analyzers 54

3.2.2 Quadrupole Mass Analyzers 57

3.2.3 Sector Mass Analyzers 67

3.2.4 Fourier-transform Mass Analyzers 70

3.3 Integrated Analytical Techniques 77

3.3.1 Hybrid Mass Spectrometers 77

3.3.2 Ion Activation Methods 82

References 85

4. Interfaces for Time-resolved Mass Spectrometry 89

4.1 Molecules in Motion 89

4.2 Time-resolved Mass Spectrometry Systems 104

4.2.1 Photochemical Processes 104

4.2.2 Off-line Interfaces 107

4.2.3 Membrane Interfaces 107

4.2.4 Electrospray Ionization 108

4.2.5 Desorption Electrospray Ionization 115

4.2.6 Other Interfaces Derived from Electrospray Ionization 116

4.2.7 Interfaces for High-throughput Screening 118

4.2.8 Interfaces Using Laser Light 118

4.2.9 Interfaces Using Plasma State 119

4.2.10 Electrochemical Mass Spectrometry 120

4.2.11 Aerosol Mass Spectrometry 121

4.2.12 Proton-transfer Reaction Mass Spectrometry 124

4.2.13 Examples of Other Interfaces 124

4.3 Concluding Remarks 126

References 127

5. Balancing Acquisition Speed and Analytical Performance of Mass Spectrometry 157

5.1 Overview 157

5.2 Spectrum Acquisition Speed 157

5.2.1 Spectrum Acquisition Time 158

5.2.2 Duty Cycle 159

5.3 Relationship between Spectrum Acquisition Time and Mass Spectrometer Performance 161

5.3.1 Mass Resolving Power 161

5.3.2 Mass Accuracy 163

5.3.3 Sensitivity and Detection Limit 165

References 167

6. Hyphenated Mass Spectrometric Techniques 169

6.1 Introduction 169

6.1.1 Chromatography 169

6.1.2 Electrophoresis 172

6.2 Separation Techniques Coupled with Mass Spectrometry 174

6.3 Ion-mobility Spectrometry 183

6.4 Other Hyphenated Systems 185

6.5 Influence of Data Acquisition Speed 187

6.6 Concluding Remarks 187

References 189

7. Microfluidics for Time-resolved Mass Spectrometry 195

7.1 Overview 195

7.2 Fabrication 195

7.3 Microreaction Systems 197

7.4 Hydrodynamic Flow 198

7.5 Coupling Microfluidics with Mass Spectrometry 200

7.6 Examples of Applications 204

7.7 Digital Microfluidics 209

7.8 Concluding Remarks 211

References 212

8. Quantitative Measurements by Mass Spectrometry 217

8.1 The Challenge of Quantitative Mass Spectrometry Measurements 217

8.1.1 (I) Instrument 218

8.1.2 (II) Sample 219

8.2 Selection of Instrument 221

8.3 Solutions to Quantitative Mass Spectrometry 221

8.3.1 Quantification with Separation 221

8.3.2 Quantification without Separation 226

8.4 Data Treatment 227

8.5 Concluding Remarks 228

References 228

9. Data Treatment in Time-resolved Mass Spectrometry 231

9.1 Overview 231

9.2 Definition of Terms 232

9.3 Spectral Patterns 232

9.3.1 Accurate Mass 233

9.3.2 Mass Calibration 235

9.3.3 Singly Charged Molecules 235

9.3.4 Multiply Charged Molecules 238

9.4 Mass Accuracy 238

9.5 Structural Derivation 240

9.5.1 Unsaturation and Ring Moieties 241

9.5.2 Nitrogen Rule 241

9.5.3 Functional Groups 241

9.6 Molecule Abundance 242

9.6.1 Signal Intensity 242

9.6.2 Quantity Calibration 243

9.6.3 Dynamic Range 244

9.7 Time-dependent Data Treatment 245

References 246

10. Applications in Fundamental Studies of Physical Chemistry 249

10.1 Overview 249

10.2 Chemical Kinetics 250

10.2.1 Quantum Chemistry 250

10.2.2 Reaction Kinetics 253

10.3 Chemical Equilibrium 259

References 263

11. Application of Time-resolved Mass Spectrometry in the Monitoring of Chemical Reactions 269

11.1 Organic Reactions 270

11.2 Catalytic Reactions 279

11.3 Photochemical Reactions 282

11.4 Concluding Remarks 284

References 284

12. Applications of Time-resolved Mass Spectrometry in the Studies of Protein Structure Dynamics 291

12.1 Electrospray Ionization in Protein Studies 292

12.2 Mass Spectrometry Strategies for Ultra-fast Mixing and Incubation 295

12.3 Hydrogen/Deuterium Exchange 296

12.4 Photochemical Methods 301

12.5 Implementation of Ion-mobility Spectrometry Coupled with Mass Spectrometry 304

12.6 Concluding Remarks 305

References 307

13. Applications of Time-resolved Mass Spectrometry in Biochemical Analysis 315

13.1 Enzymatic Reactions 315

13.1.1 Requirements of Time-resolved Mass Spectrometry in Biocatalysis 315

13.1.2 Off-line and On-line Methods 316

13.1.3 Time-resolved Mass Spectrometry Studies of Enzyme Kinetics 317

13.1.4 Application of Microfluidic Systems 322

13.1.5 Biochemical Waves 323

13.2 Time-resolved Mass Spectrometry in Systems and Synthetic Biology 324

13.3 Monitoring Living Systems 328

13.3.1 Microbial Samples 328

13.3.2 Plant and Animal Samples 329

13.4 Concluding Remarks 330

References 331

14. Final Remarks 337

14.1 Current Progress 337

14.2 Instrumentation 338

14.3 Software 339

14.4 Limitations 340

References 340

Index 341

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