Interpretation of MS-MS Mass Spectra of Drugs and Pesticides

Wilfried M A Niessen is an analytical chemist with 34 years of experience as a researcher and project manager in the field of principles, instrumentation and applications of liquid chromatography-mass spectrometry. As a consultant for hyphen MassSpec, he provided over 400 courses in more than 15 countries, as well as many consultancy projects. He was extraordinary professor bioanalytical mass spectrometry at VU University Amsterdam. He is the (co)author of more than 210 publications; over 40 book chapters; 6 books and guest-editor for 6 special volumes on mass spectrometry topics published by the Journal of Chromatography A. Ricardo A Correa C is an organic chemist who has been involved with mass spectrometry for 25 years. He runs Trans-Laboratory, a chemical analysis service provider, offering course cycles around Europe on analytical chemistry where GC-MS and LC-MS play a central role. He has developed applications which have been presented in scientific meetings in Belgium and The Netherlands, as well as coordinated the set-up of analytical chemistry laboratories overseas. He is the co-author of publications for reputed chemistry journals such as the Journal of the American Chemical Society, the Journal of Organic chemistry, the Journal of Chromatography A.

'The present book is a needed contribution in the field of tandem mass spectrometry of low molecular weight compounds in particular for the fragmentation of even electron ions formed by popular soft ionization techniques such as electrospray. The five chapters provide comprehensive insights of MS/MS spectra acquisition, characterization and interpretation. It is a unique resource to any scientist using LCMS/ MS for qualitative and quantitative analysis of drugs and pesticides.' Analytical and Bioanalytical Chemistry, November 2017

• Preface xiAbbreviations xiii1 Introduction to LC-MS Technology 11.1 Introduction 21.2 Analyte Ionization: Ion Sources 31.2.1 Electron Ionization 31.2.2 Chemical Ionization 71.2.3 Atmospheric-Pressure Ionization 131.2.4 Electrospray Ionization 161.2.5 Atmospheric-Pressure Chemical Ionization and Photoionization 201.2.6 Other Ionization Techniques 261.3 Mass Spectrometer Building Blocks 281.3.1 Introduction 281.3.2 Quadrupole Mass Analyzer 321.3.3 Ion-Trap Mass Analyzer 331.3.4 Time-of-Flight Mass Analyzer 341.3.5 Orbitrap Mass Analyzer 351.3.6 Other Mass Analyzers 361.4 Tandem Mass Spectrometry 371.4.1 Introduction 371.4.2 Tandem Quadrupole Instruments 391.4.3 Ion-Trap Instruments 401.4.4 Quadrupole-Linear Ion-Trap Hybrid Instruments 411.4.5 Quadrupole-Time-of-Flight Hybrid Instruments 411.4.6 Orbitrap Hybrid Instruments for MS-MS and MSn 411.4.7 Other Instruments for MS-MS and MSn 421.4.8 MS-MS and MSn in the Analysis of Drugs and Pesticides 431.5 Data Acquisition 431.5.1 Introduction 431.5.2 Selected-Ion and Selected-Reaction Monitoring 441.5.3 Structure-Specific Screening: Precursor-Ion and Neutral-Loss Analysis 441.5.4 Data-Dependent Acquisition 451.5.5 Data-Independent Acquisition 451.6 Selected Literature on Mass Spectrometry 452 Interpretation of Mass Spectra 552.1 Mass Spectrometry: A Nuclear Affair 552.2 Isomers, Isotones, Isobars, Isotopes 562.3 Masses in MS 582.4 Isotopes and Structure Elucidation 602.5 Nitrogen Rule, Ring Double-Bond Equivalent, and Hydrogen Rule 612.6 Resolving Power, Resolution, Accuracy 632.7 Calculating Elemental Composition from Accurate m/z 662.8 Protonated and Deprotonated Molecules and Adduct Ions 673 Fragmentation of Even-Electron Ions 713.1 Introduction 723.2 Analyte Ionization Revisited 733.3 Fragmentation of Odd-electron Ions 743.4 High-energy Collisions of Protonated Molecules 763.4.1 General Aspects 773.4.2 Selected Examples 793.5 Fragmentation of Protonated Molecules 813.5.1 Singly-Charged Peptides 823.5.2 Protonated Small Molecules: Complementary Fragment Ions 833.5.3 Fragmentation of Peptides Revisited 863.5.4 Direct-Cleavage Reactions 893.5.5 Consecutive Small-Molecule Losses 893.5.6 Other Fragmentation Reactions 893.5.7 Loss of Radicals from Even-Electron Ions 913.5.8 Skeletal Rearrangements in Protonated Molecules 923.6 Characteristic Positive-ion Fragmentation of Functional Groups 943.6.1 Cleavages of C-C Bonds 943.6.2 Alcohols and Ethers 953.6.3 Aldehydes and Ketones 963.6.4 Carboxylic Acids and Esters 963.6.5 Amines and Quaternary Ammonium Compounds 983.6.6 Amides, Sulfonyl Ureas, and Carbamates 993.6.7 Compounds containing Phosphorus or Sulfur 1013.6.8 Miscellaneous Compound Classes 1013.7 Fragmentation of Deprotonated Molecules 1023.7.1 High-Energy CID with NICI-Generated Deprotonated Molecules 1023.7.2 General Aspects 1023.7.3 Alcohols and Ethers 1023.7.4 Carboxylic Acid and Esters 1033.7.5 Amines 1043.7.6 Amides and Ureas 1043.7.7 Sulfonamides and Related Sulfones 1063.7.8 Halogenated Compounds 1073.7.9 Miscellaneous Compound Classes 1083.8 Fragmentation of Metal-ion Cationized Molecules 1083.9 Generation of Odd-electron Ions in ESI-MS, APCI-MS, and APPI-MS 1113.10 Useful Tables 1124 Fragmentation of Drugs and Pesticides 1294.1 Fragmentation of Drugs for Cardiovascular Diseases and Hypertension 1344.1.1 β-Blockers or β-Adrenergic Antagonists 1344.1.2 Dihydropyridine Calcium Antagonists 1374.1.3 Angiotensin-Converting Enzyme Inhibitors 1404.1.4 Diuretic Drugs 1424.1.5 Angiotensin II Receptor Antagonists 1484.1.6 Other Antihypertensive Compounds 1494.1.7 Antiarrhythmic Agents 1534.2 Fragmentation of Psychotropic or Psychoactive Drugs 1584.2.1 Phenothiazines 1584.2.2 Other Classes of Neuroleptic Drugs 1614.2.3 Antidepressants 1634.2.4 Benzodiazepines 1674.2.5 Local Anesthetics 1734.2.6 Barbiturates 1734.2.7 Anticonvulsant Drugs 1744.2.8 Other Psychotropic Drugs 1754.3 Fragmentation of Analgesic, Antipyretic, and Anti-Inflammatory Drugs 1794.3.1 Acetaminophen 1794.3.2 Salicylic Acid Derivatives 1794.3.3 Nonsteroidal Anti-Inflammatory Drugs 1804.3.4 COX-2 Inhibitors 1844.4 Fragmentation of Drugs Related to Digestion and the Gastrointestinal Tract 1884.4.1 Antidiabetic Drugs 1884.4.2 Antiulcer Drugs 1914.4.3 Lipid-Lowering Agents 1924.4.4 Anorexic Drugs 1954.4.5 Antiemetic Drugs 1964.5 Fragmentation of Other Classes of Drugs 1994.5.1 β-Adrenergic Receptor Agonists 1994.5.2 Histamine Antagonists 1994.5.3 Anticholinergic Agents 2024.5.4 Drugs against Alzheimer's Disease: Acetylcholinesterase Inhibitors 2044.5.5 Antiparkinsonian Drugs 2084.5.6 Antineoplastic and Cytostatic Drugs 2094.5.7 Immunosuppressive Drugs 2144.5.8 X-ray Contrast Agents 2164.5.9 Anticoagulants and Rodenticides 2184.5.10 Conclusions 2194.6 Fragmentation of Steroids 2224.6.1 Introduction 2224.6.2 Fragmentation of Steroids 2234.6.3 Fragmentation in 3-Keto-Δ4-Steroids 2244.6.4 Anabolic Steroids 2254.6.5 Progestogens 2274.6.6 Corticosteroids 2284.6.7 Estrogens 2344.6.8 Steroid Conjugates 2364.7 Fragmentation of Drugs of Abuse 2414.7.1 Introduction 2414.7.2 Amphetamine and Related Compounds 2414.7.3 Cannabinoids 2484.7.4 Cocaine and Related Substances 2504.7.5 Opiates 2514.7.6 Miscellaneous Drugs of Abuse 2524.7.7 Designer Drugs 2554.8 Fragmentation of Antimicrobial Compounds 2624.8.1 Sulfonamides 2624.8.2 Chloramphenicol and Related Compounds 2654.8.3 β-Lactams 2664.8.4 (Fluoro)quinolones 2734.8.5 Aminoglycosides 2774.8.6 Tetracyclines 2794.8.7 Nitrofurans 2794.8.8 Macrolides 2814.8.9 Miscellaneous Antibiotics 2824.9 Fragmentation of Antimycotic and Antifungal Compounds 2894.9.1 Imidazolyl Antimycotic Compounds 2894.9.2 Triazolyl Antifungal Compounds 2904.9.3 Benzamidazole Fungicides 2924.9.4 Other Classes of Fungicides 2934.10 Fragmentation of Other Antibiotic Compounds 2974.10.1 Anthelmintic Drugs 2974.10.2 Antiprotozoal, Coccidiostatic, and Antimalarial Agents 2994.10.3 Antiviral Drugs 3044.10.4 Antiseptics and Disinfectants 3094.11 Pesticides 3154.11.1 Triazine Herbicides 3154.11.2 Carbamates 3174.11.3 Quaternary Ammonium Herbicides 3224.11.4 Organophosphorus Pesticides 3224.11.5 Urea Herbicides: Phenylureas, Benzoylphenylureas, and Others 3294.11.6 Sulfonylurea Herbicides 3344.11.7 Chlorinated Phenoxy Acid Herbicides 3374.11.8 Phenolic Compounds 3394.11.9 Miscellaneous Herbicides 3395 Identification Strategies 3515.1 Introduction 3515.2 Confirmation of Identity in Following Organic Synthesis 3525.3 Confirmation of Identity in Targeted Screening by SRM-based Strategies 3535.3.1 Environmental Analysis 3545.3.2 Food Safety Analysis 3555.3.3 Sports Doping Analysis 3555.3.4 General Unknown Screening in Toxicology 3555.4 Confirmation of Identity by High-resolution Accurate-mass MS Strategies 3565.4.1 Environmental and Food Safety Analysis 3565.4.2 General Unknown Screening in Toxicology 3575.4.3 Sports Doping Analysis 3575.5 Library Searching Strategies in Systematic Toxicological Analysis 3575.6 Dereplication and Identification of Natural Products and Endogenous Compounds 3605.7 Identification of Structure-related Substances 3615.7.1 Drug Metabolites 3625.7.2 Impurities and Degradation Products 3665.8 Identification of Known Unknowns and Real Unknowns 366Compound Index 381Subject Index