Practical Aspects of Trapped Ion Mass Spectrometry, Volume V: Applications of Ion Trapping Devices (Modern Mass Spectrometry)

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CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2010 by Taylor and Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number: 978-1-4200-8373-6 (Hardback) This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright. com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Practical aspects of ion trap mass spectrometry / edited by Raymond E. March, John F.J. Todd. p. cm. -- (Modern mass spectrometry) Includes bibliographical references and index. ISBN 0-8493-4452-2 (vol. 1) 1. Mass spectrometry. I. March, Raymond E. II. Todd, John F.J. III. Series. QD96.M3P715 1995 539.7’.028’7--dc20 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com

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To ion trappers, young and old, everywhere.

Contents Preface.......................................................................................................................xi Volume IV Contents................................................................................................xxi Editors.....................................................................................................................xxv Contributors...........................................................................................................xxix

part I  Ion Reactions Chapter 1 Ion/Ion Reactions in Electrodynamic Ion Traps....................................3 Jian Liu and Scott A. McLuckey Chapter 2  Gas-Phase Hydrogen/Deuterium Exchange in QuadrupoleIon Traps.............................................................................................. 35 Joseph E. Chipuk and Jennifer S. Brodbelt Chapter 3  Methods for Multi-Stage Ion Processing Involving Ion/Ion Chemistry in a Quadrupole Linear Ion Trap....................................... 59 Graeme C. McAlister and Joshua J. Coon

Part II  Ion Conformation and Structure Chapter 4  Chemical Derivatization and Multistage Tandem Mass Spectrometry for Protein Structural Characterization........................ 83 Jennifer M. Froelich, Yali Lu, and Gavin E. Reid Chapter 5  Fourier Transform Ion Cyclotron Resonance Mass Spectrometry in the Analysis of Peptides and Proteins........................................... 121 Helen J. Cooper Chapter 6  MS/MS Analysis of Peptide–Polyphenols Supramolecular Assemblies: Wine Astringency Approached by ESI-IT-MS............. 153 Benoît Plet and Jean-Marie Schmitter

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Chapter 7  Structure and Dynamics of Trapped Ions.......................................... 169 Joel H. Parks Chapter 8  Applications of Traveling Wave Ion Mobility-Mass Spectrometry.....................................................................................205 Konstantinos Thalassinos and James H. Scrivens

part III  Ion Spectroscopy Chapter 9  The Spectroscopy of Ions Stored in Trapping Mass Spectrometers.................................................................................... 239 Matthew W. Forbes, Francis O. Talbot, and Rebecca A. Jockusch Chapter 10  Sympathetically-Cooled Single Ion Mass Spectrometry................. 291 Peter Frøhlich Staanum, Klaus Højbjerre, and Michael Drewsen Chapter 11  Ion Trap: A Versatile Tool for the Atomic Clocks of the Future!....................................................................... 327 Fernande Vedel

part IV Practical Applications Chapter 12  Boundary-Activated Dissociations (BAD) in a Digital Ion Trap (DIT)....................................................................................... 367 Francesco L. Brancia, Luca Raveane, Alberto Berton, and Pietro Traldi Chapter 13  The Study of Ion/Molecule Reactions at Ambient Pressure with Ion Mobility Spectrometry and Ion Mobility/ Mass Spectrometry.......................................................................... 387 Gary A. Eiceman and John A. Stone Chapter 14  The Role of Trapped Ion Mass Spectrometry for Imaging.............. 417 Timothy J. Garrett and Richard A. Yost

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Chapter 15  Technology Progress and Application in GC/MS and GC/MS/MS................................................................. 439 Mingda Wang and John E. George III Chapter 16  Remote Monitoring of Volatile Organic Compounds in Water by Membrane Inlet Mass Spectrometry................................ 491 Romina Pozzi, Paola Bocchini, Francesca Pinelli, and Guido C. Galletti Author Index.........................................................................................................509 Subject Index......................................................................................................... 513

Preface This monograph is Volume V of a miniseries devoted to (i) practical aspects of applications of mass spectrometry for the study of gaseous ions confined in ion traps, and (ii) treatments of the theory of ion confinement in each ion-trapping device. Volumes I–III were published in 1995 under the title Practical Aspects of Ion Trap Mass Spectrometry. Volume III, Chemical, Environmental and Biomedical Applications, is a ­companion to Volumes I and II, subtitled Fundamentals of Ion Trap Mass Spectrometry and Ion Trap Instrumentation, respectively. Volumes I–III are concerned principally with the history, theory, and applications of the quadrupole ion trap and, to a lesser degree, of the quadrupole mass filter. Volume V, published in 2009 under the title Practical Aspects of Trapped Ion Mass Spectrometry, and subtitled Applications, is a compa­ nion to Volume IV, subtitled Theory and Instrumentation. The contents of Volume IV are given following the conclusion of this preface. The history of the quadrupole ion trap was presented in tabular form in Chapter 2 of Volume I as “The Ages of the Ion Trap” and, upon revisiting this table, one is struck by the spectacular progress that has been made in the ion-trapping field since 1995. In the Preface to Volume II, we noted two exceptional landmarks in this history: first, the invention of the quadrupole ion trap (and quadrupole mass filter) by Wolfgang Paul and Hans Steinwedel, which was recognized by the award of the 1989 Nobel Prize in Physics, in part, to Wolfgang Paul and Hans Dehmelt; and, second, the discovery announced in 1983 of the mass-selective instability scan by George C. Stafford, Jr. On these two landmarks rested the entire field of ion trap mass spectrometry. One of the table entries for 1990 was “Electrospray Ionization (Van Berkel, Glish, and McLuckey),” and Chapter 3 of Volume II was devoted to “Electrospray and the Quadrupole Ion Trap.” A ­further contribution, entitled “Electrospray/Ion Trap Mass Spectrometry – Applications,” by Hung-Yu Lin and Robert D. Voyksner, appeared as Chapter 14 in Volume III. The advent of electrospray ionization and its ready compatibility with ion-trapping devices has brought about a revolution in the accessibility of covalent compounds for examination by mass spectrometry in general and by quadrupole ion trap mass spectrometry in particular. For their development of soft desorption ionization methods for mass spectrometric analyses of biological macromolecules, John Fenn and Koicho Tanaka received the Nobel Prize in Chemistry for 2002. We add our ­congratulations and thanks to these Nobelists and to those from the mass spectrometry community. The enormous impact that electrospray ionization has made in biochemistry in general, and in the study of proteins in particular, is remarkable. Virtually every mass spectrometry laboratory is now equipped with electrospray ionization; compounds for which derivatization was previously essential for examination by electron impact can now be examined facilely in solution by direct infusion to an electrospray ionization source. As testament to this situation, more than half of the chapters presented in Volumes IV and V are concerned with the use of electrospray ionization. The practice of trapping gaseous ions and the applications thereof have expanded considerably during the past decade or so, in part due to the use of electrospray xi

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ionization but also as witnessed by the substantial growth in popularity of quadrupole ion traps and of Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometers, instruments that hitherto were regarded as being rivals rather than complementary technologies. In addition, we have seen the nascence of new ­methods for trapping ions, such as the Orbitrap™, the digital ion trap (DIT), the rectilinear ion trap (RIT), and the toroidal ion trap. Furthermore, during this period, there have been significant advances in the development and application of the quadrupole ion trap and of the quadrupole mass filter, both standalone and in concatenation with other mass spectrometric instruments, for example, with Fourier transform ion cyclotron resonance and with time-of-flight (TOF) mass spectrometers. New and/or modified existing methods for ion processing have been developed and applied; these methods include electron capture dissociation (ECD), electron transfer dissociation (ETD), charge inversion, proton transfer reaction (PTR), electron transfer (ET), and ion attachment (IA). Other recent advances involving the coupling of ion mobility spectrometry (IMS) with mass spectrometry have brought about the introduction of high-field asymmetric waveform ion mobility spectrometry (FAIMS) and traveling wave ion mobility mass spectrometry (TWIM-MS). Indeed, so many advances have occurred in the ion-trapping field that we needed to consider a somewhat broader definition of ion trapping compared with what has been employed hitherto; after several iterations, we arrived at the definition proposed in Section 1.1 of Volume IV, “an ion is ‘trapped’ when its residence time within a defined spatial region exceeds that had the motion of the ion not been impeded in some way.” Clearly, this definition includes those various forms of ion mobility spectrometry mentioned above. Armed with this definition of ‘trapped ions,’ it seemed appropriate to the editors that a further volume in this mini-series could be undertaken, not limited to quadrupole devices but encompassing advances in all aspects of trapped ion mass spectrometry. When a commercial product has achieved a degree of market acceptance, which we believed was the case for the three volumes of Practical Aspects of Ion Trap Mass Spectrometry, one is reluctant to lose the connectivity within the miniseries upon embracing an expansion of the field in question. Fortunately, a minor word change to Practical Aspects of Trapped Ion Mass Spectrometry saved the day. With this small but significant change in title, the expanded field could be considered and included within the ‘practical aspects of ion trapping’ rubric. The collective response to our subsequent approaches to potential authors in the expanded ion-trapping field was near overwhelming, so much so that in fact two monographs, Volumes IV and V, have resulted from this endeavor. Volume IV is entitled Theory and Instrumentation and is composed of six parts: Fundamentals, New Ion Trapping Techniques, Fourier Transform Mass Spectrometry, Quadrupole Rod Sets, 3D-Quadrupole Ion Trap Mass Spectrometry, and Photochemistry of Trapped Ions. Volume V is entitled Applications and features four parts: Ion Reactions, Ion Conformation and Structure, Ion Spectroscopy, and Practical Applications. Part 1. Ion Reactions is composed of three chapters in which ion reactions, that is,  ion/neutral reactions or ion/ion reactions, are examined. Several ion-trapping devices have the capability for examining reactions of ions with neutral species and other ionic species where the extent of the reaction is monitored by the mass

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spectrometric function of the instrument. The quadrupole, or electrodynamic, ion trap is inherently compatible with the study of ion/ion reactions due to its unique ability to store simultaneously ions of both polarities in overlapping regions of space. In Chapter 1 is presented a review of the instrumental requirements for the study of ion/ion reactions. Particular emphasis is given to the use of an electrodynamic ion trap for the study of multiply-protonated peptide molecules with anions. The trapped ions assume characteristic sets of m/z-dependent frequencies of motion in the oscillating quadrupole field of the ion trap, which allows ready manipulation of ions for ion isolation and activation, both of which are common elements in a tandem mass spectrometric experiment. The ‘tandem-in-time’ nature of the ion trap MSn experiment provides well-defined conditions for ion/ion reactions and permits determination of ion genealogy. A bath gas, such as helium at ca 1 mTorr, intended originally to cool the ions to the center of the trap so as to enhance both sensitivity and mass resolution upon mass analysis, improves ion/ion reaction efficiencies by maximizing the spatial overlap and minimizing the translational energies of the two ion clouds. Chapter 2 is focused on a particular type of ion/neutral reaction, namely that in which hydrogen atoms in the ion exchange with deuterium in the neutral reaction partner. The quadrupole ion trap mass spectrometer is well suited for investigations of such hydrogen/denterium (H/D) exchange reactions because the kinetics of reactions can be monitored accurately by varying the ion storage time. As illustrated in this chapter, applications of H/D exchange in quadrupole ion traps range from those involving small organic molecules, especially involving comparisons of isomers, to larger biological molecules for which conformational effects play a significant role. Chapter 3 considers the prospect of utilizing multiple ion-manipulation methodologies, which are available with ion trap mass spectrometers, to achieve whole protein sequence analysis; such analysis is described as top-down proteomics. The basis of this approach is the implementation of multi-functional tools for systematic ion manipulation and processing, where ion/ion reactions such as electron transfer, proton transfer, and ion attachment, represent one family of such tools. These technologies are inter-meshed with conventional ion trap processing methodologies of ion isolation and collision-induced dissociation. Concatenation of MSn scan functions from these individual components can constitute a versatile approach that promises to accelerate markedly the field of large molecule mass spectrometry. The practical application of these processing methodologies in a linear ion trap requires modification of the ion trap electronics to allow for the superimposition of a radiofrequency voltage on the end lenses, which allows for charge-sign independent trapping. Part 2. Ion Conformation and Structure presents discussions of structural characterization of proteins and peptides using quadrupole ion trap mass spectrometry, Fourier transform ion cyclotron resonance mass spectrometry, and the novel method known as traveling wave ion mobility mass spectrometry. In addition to the observation of collective fluctuations of the molecular substructures within biomolecules, the organization of atoms in small ion clusters is investigated using electron diffraction. In Chapter 4 is discussed the ‘bottom-up’ or ‘shotgun’ tandem mass spectrometric approach to protein identification and characterization, which is the complementary method to top-down proteomics that is discussed in Chapter 3. In order to overcome the limitations of bottom-up proteomics, chemical derivatization strategies are

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explored that direct the fragmentation of protonated peptides to the formation of sequence product ions. Such strategies can be employed to direct fragmentation to the formation of non-sequence product ions. Chapter 5 provides an overview of Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry and its applications in the structural characterization of peptides and proteins. The principles of FT-ICR, that is, ion motion, ion excitation/ detection, and instrumental considerations, are discussed and an explanation of the features of FT-ICR that make it so suitable for peptide/protein analysis is presented. New methods for the fragmentation of peptide and protein ions in FT-ICR mass spectrometry, such as sustained off-resonance irradiation collision-induced dissociation (SORI-CID), infrared multiphoton dissociation (IRMPD), blackbody infrared radiative dissociation (BIRD), surface-induced dissociation (SID), and electron capture dissociation (ECD), are described in detail. Innovative hybrid FT-ICR instruments, which have recently become available, are reviewed. In conclusion, the chapter discusses the applications of FT-ICR in ‘bottom-up’ and ‘top-down’ proteomics. Chapter 6 is devoted to the tandem mass spectrometric investigation of supramolecular assemblies of peptides with non-covalently-bonded polyphenols. The quest of the specific investigation recounted in this chapter was to gain insight at a molecular level into the interaction of polyphonies with proline-rich peptides, and to develop a future analytical methodology for the evaluation of astringency, specifically the astringency of wine. Two relevant points of interest are (i) polyproline peptides are subjects of intensive study, as is shown in the following chapter, Chapter 7, and (ii) the chemistry of proteins with non-covalently-bonded ligands is under examination because of the possibility of facile transport of ubiquitous compounds of doubtful environmental value into organs such as the liver. Analysis of these supramolecular assemblies of proline-rich peptides with a wide range of flavonoids (polyphenols), by means of energy-resolved mass spectrometry (ERMS), led to the creation of a relative affinity scale of the proline-rich peptides for the flavonoids examined. Chapter 7 describes quadrupole ion trap studies of the organization of atoms in small ion clusters and the observation of collective fluctuations of the molecular substructures within biomolecules. The introduction of new ion sources, in particular metal-cluster aggregation sources and electrospray ionization, have provided unique opportunities to produce ion beams composed of metal atom clusters and biomolecules, respectively. Metal clusters are formed with a single charge but in a broad array of masses corresponding to the number of atoms, whereas biomolecular ions are generated for a single species in an ensemble of charge states. These studies take advantage of the advances in ion trap technology for flexible and reliable ion-cloud manipulation of higher mass ions required for the electron diffraction of, for example, Ag55+ and Au21−, and for fluorescence measurements of dye-derivatized polyproline peptides. The results presented here enunciate clearly the ways in which these methods have contributed to our understanding of how the atoms are organized in small metal clusters and of the temperature dependence of local fluctuations of biomolecular conformations. In a drift cell, ions migrate through a counter-flowing buffer gas in the presence of a low electric field. The use of the drift cell in this manner is often referred to as ion mobility spectrometry (IMS), which is now a well-established analytical technique that is employed throughout the world for the detection of explosives, drugs, and

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chemical warfare agents. Ion mobility measures the time it takes for ions to traverse a drift tube. Ion separation occurs as a result of interactions between these ions and the buffer gas; the extent of separation depends not only on the mass and charge, as may be anticipated, but on the shape (or conformation) of the ion, which is unique to ion mobility spectrometry. The study of ion/molecule reactions in IMS is discussed in Chapter 13. Two alternative approaches have been introduced recently; these are high-field asymmetric waveform ion mobility spectrometry (FAIMS) and traveling wave ion mobility spectrometry (TWIMS). In Volume IV, Chapter 5 was devoted to a discussion of FAIMS. In Chapter 8 is presented an account of traveling wave ion mobility spectrometry. Unlike drift cell ion mobility experiments, where a constant low electric field is applied to the mobility cell, traveling wave ion mobility spectrometry uses a traveling wave comprising a series of transient direct current voltages to propel ions through a stacked-ring ion guide (SRIG) to which radiofrequency voltages have been applied to consecutive electrodes. The SRIG consists of a series of ring electrodes that are arranged orthogonally to the ion transmission axis, and opposite phases of radiofrequency voltage are applied to adjacent rings. When a transient direct current potential, superimposed upon this radiofrequency potential, is applied to one pair of adjacent ring electrodes, ions are propelled through the SRIG. The transient direct current potential moves along ring electrode pairs across the length of the SRIG at regular time intervals, generating a sequence of traveling waves (T-Waves). This particular configuration of SRIG is referred to as a traveling wave ion guide (TWIG). A concatenation of three TWIGs has been incorporated within a Q-TOF geometry to create the Synapt™ HDMS system, a commercial instrument incorporating ion mobility separation. Most applications using the Synapt have focused on studying the conformation of proteins and protein complexes. Among the applications discussed here is a study of the prion protein, a fibril-forming protein involved in prion diseases. Prions are a class of fatal, infectious, neurodegenerative diseases that affect both humans and animals. Part 3. Ion Spectroscopy. In Chapter 9, we return to the theme of ion photodissociation, which was included also in Volume IV, Part 6, in an exploration of trapped-ion photodissociation, electron photodetachment, and fluorescence. Trapped-ion fluorescence may offer an alternative approach for the elucidation of ion conformation. Whereas these spectroscopic experiments require high ion densities, much attention is directed to the spectroscopic study of single ions confined in an ion trap. Chapters 10 and 11 are illustrative of such studies, with the former devoted to the study of a single molecular ion in a linear ion trap and the latter to a single atomic ion in P ­ aul-type ion traps. While both types of studies require extensive cooling of the subject ion, once such cooling has been achieved, the ions can remain confined for many hours. Chapter 9 contains a discussion of practical aspects of experimental design for the pursuit of photodissociation, electron photodetachment, and fluorescence of trapped, mass-selected organic ions. A review is given of the wide range of possible spectroscopic experiments that can be combined fruitfully with the ion storage and massselective capabilities provided by ion-trapping devices for the scrutiny of molecular ions. Details of the modification of a quadrupole ion trap together with the results from extensive modeling of the apparatus are presented. Photodissociation is the

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fragmentation of an ion due normally to the absorption of light in a narrow wavelength range. In this chapter, the excitation source is stepped or scanned through a range of wavelengths, while monitoring ion intensities as a function of excitation wavelength, in order to construct an optical spectrum. When the extent of photodissociation is monitored as a function of excitation wavelength, the process is termed ‘action’ or ‘consequence’ spectroscopy. The application of action spectroscopy, which has been used to generate vibrational (infrared) and vibronic ­(ultraviolet-visible) spectra of mass spectrometric precursor and product ions, is discussed. Fluorescence spectroscopy, in which radiative emission from activated ions can be monitored using a photon detector, is shown here to be highly sensitive to a chromophore’s local environment, making it an excellent probe of ion conformation. In Chapter 10, the novel technique of sympathetically-cooled single ion mass spectrometry (SCSI-MS) is described; this technique relies on the measurement of the resonant excitation frequency of one of the two oscillatory modes of a trapped and crystallized linear two-ion system consisting of one laser-cooled atomic ion of known mass and the a priori unknown atomic or molecular ion, whose mass is to be determined. The mass of the unknown ion can be deduced from this measured frequency. The crystallization of the two-ion system results from the sympathetic cooling of the unknown ion through the Coulomb interaction with the laser-cooled ion; the two-ion system is aligned along the axis of the linear ion trap. Resonant excitation can be promoted by applying a sinusoidally-varying electric field along this axis. The ­resonance frequencies are determined by monitoring fluorescence from the laser-cooled ion while scanning the period of the applied driving force. When the period is equal to the period of one of the two oscillatory modes of the two-ion system, that is, the centerof-mass mode where the ions move in phase, or the breathing mode where the ions move with opposite phase, the motion of the ions becomes highly excited. Examples of molecular ions examined here are CaO+, MgD+, and MgH+. Chapter 11 gives a review of atomic clocks of the future using single ions confined in relatively small ion traps; small or miniature ion traps have been discussed in Volume IV, Chapter 2. The purpose of Chapter 11 is to expound upon the specific topic of atomic clocks utilizing ion traps and the new challenges engaged presently for the measurement of time with extremely high precision. A major part of physics is dedicated permanently to the enhancement of measurement and more precise definitions of the fundamental units. Among them, the time unit, the second, is one of the most crucial units necessary for the advancement of knowledge. The time unit was the first for which the definition put aside any material systems in that Greenwich Mean Time (GMT) was defined, in 1884, on the assumption that one second is equal to 1/86,400 of the mean solar day. As most of the fundamental constants can be related either to a time or to a frequency measurement, the quest for the detection of the smallest possible time variation in these constants, that is, the attainment of a time variation measurement of these constants at the 10 −17–10−18 level, is being continued. Highly accurate clocks are not merely a convenience; they are a necessity for such fundamental problems as the local position invariance, baseline interferometry, observation of the so-called ‘gravitational red-shift’, and for the ground-positioning system (GSP)-Galileo systems that require a panoply of atomic clocks located in satellites as well on the Earth’s surface. All of the current

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research into types of ion clocks and their development are covered explicitly in this chapter. Part 4. Practical Applications presents five practical examples of trapped-ion technology that reflect the wide diversity of applications of trapped-ion devices. Yet there is a common thread that links these applications, and it is the existence of such a thread that justifies the publication of the Volume IV and Volume V ­monographs. This common thread links the efforts, foresight, and business acumen of manufacturers with the knowledge and experimental skills of researchers to bring forth ­instruments at an affordable price that will enhance and protect the well-being of mankind. Such a claim is not an overstatement, as is shown by the final three ­chapters, Chapters 14–16. In the Preface to the first edition of Quadrupole Storage Mass Spectrometry,* a monograph that may be familiar to some of the more curious graduate students, we wrote “There is now abundant evidence of the application to the health services of mass spectrometric techniques with concomitant high sensitivity and resolution for toxicological studies; studies of metabolism and incipient disease; environmental problems; the quality of food, well water, and materials; forensic sciences; and so forth. Thus, the advent of the ion trap detector permits a much greater use of mass spectrometric techniques not only in the technically developed countries but also in those countries which are technically less advanced.” Chapter 12 affords an example of industry–university cooperation with a description of the commercially-available digital ion trap, which is the subject of Chapter 4 in Volume IV, employed for the fragmentation of mass-selected ions by boundary-activated dissociation, a technique that was discovered in an academic research laboratory. Chapter 13 gives an account of the utilization of ion mobility spectrometry and ion mobility/mass spectrometry for the study of basic ion/molecule reactions at ambient pressure, which is the pressure regime used commonly for the detection of explosives, drugs, and chemical warfare agents. Chapter 14 is concerned with a novel application, that of imaging mass spectrometry wherein thin tissue sections are analyzed directly and permit the creation of chemically-selective images of intrinsic chemical distributions. This technique allows characterization of known compounds from a variety of tissues, and the identification of unknown chemical signatures for a variety of studies such as disease progress or pharmaceutical studies. Chapter 15 permits a review of the progress made in the instrumentation for gas chromatography/ion trap mass spectrometry since the introduction by Finnigan MAT of the first commercial gas chromatograph/Ion Trap Detector™. Ion traps have found an important application as in situ chemical analyzers for a broad range of fields such as homeland security, ­industry, and environmental monitoring applications. Such devices can be used in marine science, where there is a high demand for monitoring natural compounds and the ever-increasing quantities of compounds of anthropogenic origin that enter rivers, lakes, and oceans. Chapter 16 presents a detailed account of the prolonged remote monitoring of volatile organic compounds in field waters by membrane inlet mass spectrometry (MIMS) using a quadrupole ion trap.

∗ March R.E., Hughes R.J., Todd J.F.J., Quadrupole Storage Mass Spectrometry, 1989. New York, Wiley

Interscience.

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Chapter 12 describes the novel operation of a digital ion trap (DIT) for the determination of the boundaries of the stability diagram and for the utilization of boundary-activated dissociation. Ion motion in a Paul or quadrupole ion trap driven by a rectangular wave quadrupolar field was described in the early 1970s, but it was not until 2000 that the mass-selective resonance method with the ion secular frequency under digital operation conditions was described. The circuits of the ­digital ion trap switch very rapidly between discrete direct current high voltage levels in order to generate the trapping waveform voltage applied to the ring electrode. An alternative ion activation method, boundary-activated dissociation, proposed in 1991, entails moving the working point (that is, the point (az, qz) on a quadrupole ion trap stability diagram defined by the magnitudes of the trapping parameters az and qz) of a mass-selected ion species close to one of the boundaries of the stability diagram. This method can be realized with the combined effect of suitable direct current and radiofrequency potentials applied to the ion trap electrodes. Under these conditions, dissociation of the mass-selected ion species can be induced. In order to evaluate the performance of the digital ion trap for boundary-activated dissociation experiments, the real shape of the stability diagram needed to be determined. As an ion species undergoes fragmentation when its working point is moved close to a stability boundary, this behavior was used to map the boundaries of the stability diagram for a digital ion trap. In the digital ion trap, variation of the duty cycle of the rectangular waveform readily allows the introduction of the direct current component for boundary-activated dissociation experiments. Regrettably, direct current power supplies are no longer made available in commercial ion trap instruments. Chapter 13 gives an introduction to the principles of ion mobility spectrometry, together with an overview of the type of information obtainable from ion mobility studies at atmospheric pressure and the variety of experimental methods employed in such studies. It is shown that thermodynamic data, which are obtainable from these studies and are suitable for tabulation, include standard enthalpies, entropies, and free energies; such data, when obtained at a specified temperature, can be regarded as universally applicable when all participants are at thermal equilibrium. Thermal equilibrium is established readily in an ion mobility spectrometer at ambient pressure because each ion experiences more than 1010 collisions per second with neutral atoms or molecules of the supporting gas atmosphere. In ­addition, the residence time of an ion in an ion mobility spectrometer operating at atmospheric pressure is ca 5–50 ms, which allows the study of the interactions of ions with molecules at very low concentrations. Illustrated here is the further advantage of thermochemical determinations obtained by ion mobility spectrometry in that the available temperature range, from sub-ambient to more than 500 K, is far greater than that available with many other experimental methods. In the lower electrostatic field conditions of ion mobility spectrometry, thermal conditions always prevail for ions. Hence, this technique permits ready determination of ion/molecule reaction rate constants, including those for clustering reactions, for both positive and negative ions, in the temperature range from below ambient to at least 600 K. Electron association and detachment reactions are studied more easily in an ambient pressure ion mobility spectrometer than the more conventional swarm-beam method.

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In Chapter 14 is described the principles and instrumental approaches of ­imaging mass spectrometry; it also provides real-world examples of the capabilities of quadrupole ion traps (QITs) and linear ion traps (LITs) for modern imaging mass spectrometry. Imaging mass spectrometry permits direct analysis of thin tissue sections from which chemically-selective images of intrinsic chemical distributions are created. Imaging mass spectrometry using matrix-assisted laser desorption/ionization (MALDI) provides the ability to characterize and to localize compounds within tissue sections, identifying potential but unknown markers of diseases such as cancer, or to determine where an administered drug (and its metabolites) has localized in a tissue section. An advantage that mass spectrometry provides to the field of imaging is the identification of non-targeted compounds. In a typical fluorescence experiment, a fluorophore must be administered that binds to a given compound for ready identification of that specific compound. With imaging mass spectrometry, the targeted compound can be localized and other compounds that may localize with the targeted compound can be identified, thus providing a more complete understanding of the chemical signature of the specific state under investigation. Examples are discussed of the remarkable utility of sequential tandem mass spectrometry to effect MSn for the identification and structural characterizations of compounds from intact tissues. In addition, MSn is invaluable for the identification of isobaric ions: for example, m/z 828 in one sample was shown to consist of four isobaric ions and each was identified using MS3. Chapter 15 is devoted to a review of the development of the quadrupole ion trap as a detector for compounds eluting from a gas chromatograph, together with an account of the progress made by Varian Inc. in ion trap technology for gas chromatography/ mass spectrometry and gas chromatography/tandem mass spectrometry. Described here is the new type of non-linear ion trap, that is, the field is made non-linear by the superimposition of a dipole and higher-order multipoles upon the quadrupole field by a switchable electric circuit. A detailed discussion of ion traps with ­electrically-induced non-linear fields is given in Volume IV, Chapter 14. In the ion trap, both dipole and quadrupole supplemental fields are applied to the two end-cap electrodes with their frequencies tuned to βz = 2/3; the resonance of each ion species in turn with both the dipole and quadrupole supplemental fields results in improved mass resolution, higher scan speed, and extended charge capacity. Electron impact ionization and chemical ionization, within the ion trap and external to it, are discussed. The chapter is replete with many examples of applications and contains 47 figures. Chapter 16 describes the monitoring of some 16 volatile organic compounds that are included in the European Union Directive 98/83 and classified as being potentially deleterious to human health when present in drinking water. The technique employed was that of membrane inlet mass spectrometry (MIMS) combined with a quadrupole ion trap. While this technique is well known for its simplicity and sensitivity, no ­previous account has been published of the implementation of this technique to work unattended for months. Four instruments were deployed in unmanned sites, where they monitored volatile organic compounds (VOCs) in natural waters and wastewater during a period exceeding 1 year for each instrument. The instruments were equipped with software that facilitated the automatic operation of each analysis, the identification and quantitation of VOCs from the raw mass spectra, and the transmission of the results to a remote control room via an Internet connection. In the remote control

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room, a personal computer displayed the results as bar graphs and was programed to activate alarms when set concentration thresholds were exceeded. The chapter discusses laboratory performance and field performance: the former in terms of sensitivity, reproducibility, linearity tests, and comparison with purge-and-trap combined with gas chromatography/mass spectrometry; and the latter in terms of data output, most frequent maintenance operations and technical failures, and overall stability of the four remotely-controlled instruments. The longest period of unattended remote monitoring was of 526 days, of an industrial wastewater treatment plant. We wish to thank the many people who have assisted us in one way or another with myriad tasks that must be carried out in order to arrive at the publication of a monograph from a collection of manuscripts in a variety of formats and styles. First of all, to our contributors, without whom this monograph would not have appeared in print. We give thanks for their individual inspiration; we thank them for the fruits of their labors, and for their patient toleration of the idiosyncrasies of our editing, often involving repeated iterations between the two of us and the authors themselves. The 16 chapters that constitute Volume V have originated from 36 authors and ­co-authors; a total of 91 authors and co-authors contributed to Volumes IV and V. For many of these co-authors this project has been a novel experience, thus we thank our lead authors for responding to our urging that they collaborate with young scientists in their laboratories. From where else will the monographs of tomorrow originate? At CRC Press, we thank Fiona Macdonald, Pat Roberson, Rachael Panthier, Lindsey Hofmeister, Hilary Rowe, and Jennifer Derima; at Datapage, we thank Ramkumar Soundararajan, the Project Manager. Finally, we express our sincere appreciation for the tolerance of our respective spouses, Kathleen March and Mavis Todd, and for their patience, support, and sacrifices while this project, known informally as ‘PRATIMS’, took over our lives. Raymond E. March John F.J. Todd

Volume IV Contents Practical Aspects of Trapped Ion Mass Spectrometry Volume IV: Theory and Instrumentation Edited by Raymond E. March and John F.J. Todd Table of Contents part I  Fundamentals Chapter 1.

An Appreciation and Historical Survey of Mass Spectrometry Raymond E. March and John F.J. Todd

Chapter 2.

Ion Traps for Miniature, Multiplexed and Soft Landing Technologies Scott A. Smith, Chris C. Mulligan, Qingyu Song, Robert J. Noll, R. Graham Cooks, and Zheng Ouyang

Part II  New Ion Trapping Techniques Chapter 3.

Theory and Practice of the Orbitrap™ Mass Analyzer Alexander Makarov

Chapter 4.

Rectangular Waveform Driven Digital Ion Trap (DIT) Mass Spectrometer: Theory and Applications Francesco Brancia and Li Ding

Chapter 5.

High-Field Asymmetric Waveform Ion Mobility Spectrometry Randall W. Purves

Chapter 6.

Ion Traps with Circular Geometries Daniel E. Austin and Stephen A. Lammert xxi

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part III  Fourier Transform Mass Spectrometry Chapter 7 Ion Accumulation Approaches for Increasing Sensitivity and Dynamic Range in the Analysis of Complex Samples Mikhail E. Belov, Yehia M. Ibrahim, and Richard D. Smith Chapter 8 Radio Frequency-Only-Mode Event and Trap Compensation in Penning Fourier Transform Mass Spectrometry Adam M. Brustkern, Don L. Rempel, and Michael L. Gross Chapter 9 A Fourier Transform Operating Mode Applied to a ThreeDimensional Quadrupole Ion Trap Y. Zerega, J. Andre, M. Carette, A. Janulyte, and C. Reynard

part IV  Quadrupole Rod Sets Chapter 10 Trapping and Processing Ions in Radio Frequency Ion Guides Bruce A. Thomson, Igor V. Chernushevich, and Alexandre V. Loboda Chapter 11 Linear Ion Trap Mass Spectrometry with Mass-Selective Axial Ejection James W. Hager Chapter 12 Axially-Resonant Excitation Linear Ion Trap (AREX LIT) Yuichiro Hashimoto

part V  3D-Quadrupole Ion Trap Mass Spectrometry Chapter 13 An Examination of the Physics of the High-Capacity Trap (HCT) Desmond A. Kaplan, Ralf Hartmer, Andreas Brekenfeld, Jochen Franzen, and Michael Schubert Chapter 14 Electrically-Induced Nonlinear Ion Traps Gregory J. Wells and August A. Specht

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Chapter 15 Fragmentation Techniques for Protein Ions Using Various Types of Ion Trap J. Franzen and K. P. Wanczek Chapter 16 Unraveling the Structural Details of the Glycoproteome by Ion Trap Mass Spectrometry Vernon Reinhold, David J. Ashline, and Hailong Zhang Chapter 17 Collisional Cooling in the Quadrupole Ion Trap Mass Spectrometer (QITMS) Philip M. Remes and Gary L. Glish Chapter 18 ‘Pressure Tailoring’ for Improved Ion Trap Performance Dodge L. Baluya and Richard A. Yost Chapter 19 A Quadrupole Ion Trap/Time-of-Flight Mass Spectrometer Combined with a Vacuum Matrix-Assisted Laser Desorption Ionization Source Dimitris Papanastasiou, Omar Belgacem, Helen Montgomery, Mikhail Sudakov, and Emmanuel Raptakis

part VI Photochemistry of Trapped Ions Chapter 20 Photodissociation in Ion Traps Jennifer S. Brodbelt Chapter 21 Photochemical Studies of Metal Dication Complexes in an Ion Trap Guohua Wu, Hamish Stewart, and Anthony J. Stace

Editors Raymond E. March, PhD, DSc, D(hc), FCIC, is presently Professor Emeritus of Chemistry at Trent University in Peterborough, ON, Canada. He obtained a BSc (Hons) in Chemistry from Leeds University in 1957; a PhD from the University of Toronto in 1961 (supervised by Professor John C. Polanyi, Nobelist 1986); a DSc from Leeds University in 2000; and an honorary doctorate (D(hc)) from l’Université de Provence in 2008. From 1954 to 1957, he was a Cadet Pilot in the Leeds University Air Squadron Royal Air Force Volunteer Reserve (RAFVR) and, from 1958 to 1963, a Flight Lieutenant in the Royal Canadian Air Force (Auxiliary) (RCAF). From 1960 to 1961, he held a Canadian Industries Limited Research Fellowship. From 1962 to 1963, he was a Post-Doctoral Fellow with Professor H.I. Schiff at McGill University, and a Research Associate from 1963 to 1965, during which time he lectured at McGill University and Loyola College. In 1965, he joined the faculty of Trent University where he has conducted independent research for some 44 years in gas-phase kinetics, optical spectroscopy, gaseous ion kinetics, analytical chemistry, nuclear magnetic resonance spectroscopy, and mass spectrometry. Kathleen and Ray have been married for 51 years; they have three daughters, Jacqueline, Roberta, and Sally with spouses Paul, Stuart, and Lauren, respectively, and nine grandchildren, Shawn, Jessica, Thomas, Daniel, Rebecca, Sara, James, Madeline, and Carson, in order of appearance. Dr. March has published and/or co-authored over 170 scientific papers and some 75 conference presentations in the above areas of research with emphasis on mass spectrometry, both with sector instruments and quadrupole ion traps. Dr. March is a co-author with Dr. Richard J. Hughes and Dr. John F.J. Todd of Quadrupole Storage Mass Spectrometry, published in 1989. A second edition of Quadrupole Storage Mass Spectrometry, co-authored by Dr. March and Dr. John F.J. Todd was ­published in 2005. Dr. March and Dr. John F.J. Todd co-edited three volumes entitled Practical Aspects of Ion Trap Mass Spectrometry, published in 1995. Volume IV in the series Practical Aspects of Trapped Ion Mass Spectrometry is in press. Dr. March is a ­co-author with Oscar V. Bustillos and André Sassine of A Espectrometria de Massas Quadupolar, published in Portuguese in 2005. Professor March is a Fellow of the Chemical Institute of Canada and a member of the American, British, and Canadian Societies for Mass Spectrometry. In 2009, he received the Gerhard Herzberg Award of the Canadian Society for Analytical Sciences and Spectroscopy (CSASS). In

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1995, he received the Distinguished Faculty Research Award from Trent University, and the Canadian Mass Spectrometry Society presented him with the Recognition Award and, in 1997, with the Distinguished Contribution Award. Dr.  March is a member of the Editorial Advisory Boards for Rapid Communications in Mass Spectrometry, the Journal of Mass Spectrometry, and the International Journal of Mass Spectrometry. In 1975, Dr. March was an Exchange Fellow (NRC-CNRS) at Orsay, France, with Professor Jean Durup; in 1983, an Exchange Fellow (NRCRoyal Society of London) in Swansea, Wales, with Professor J.H. Beynon; in 1989 and 1992, a Visiting Professor, Université de Provence, Marseille, France, with Prof Fernande Vedel; in 1993 and 1995, a CNRS Visiting Professor, Université Pierre et Marie Curie, Paris, France, with Prof Jean-Claude Tabet; and in 1999, a Visiting Professor, Université de Provence, Marseille, France, with Yves Zerega. In 1987, Dr. March was a Distinguished Lecturer at the Universities of Berne, Neuchatel, and Lausanne, in Switzerland. Dr. March’s research in the field of mass spectrometry and gas-phase ion chemistry involved the development and application of mass spectrometric instruments, particularly quadrupole ion trap mass spectrometers and hybrid mass spectrometers, for both fundamental studies and the formulation of analytical protocols for the determination of compounds of environmental interest. His current research interests are focused within Trent University’s Water Quality Centre (www. trentu.ca/wqc/). As a founding member of the Water Quality Centre his principal research interest lies in the mass spectrometric and nuclear magnetic resonance spectroscopic investigation of natural compounds that, having been formed by plants, may enter waterways and/or the water table. His current research involves the study of flavonoids and flavonoid glycosides; such compounds are often found in those products that have become known as neutraceuticals. Electrospray ionization combined with tandem mass spectrometry permits the investigation of ion fragmentation at high mass resolution and the derivation of possible ion fragmentation mechanisms using ion structures; these studies are supported by theoretical calculations carried out in collaboration with Professor E.G. Lewars. An important aspect of this research is the development of appropriate analytical protocols for flavonoid glycosides in water and in plant extracts. Nuclear magnetic resonance (NMR) studies of flavonoids and metabolites, carried out in collaboration with Professor D.A. Ellis and Dr. D.C. Burns, have permitted a rationalization of chemical shifts with product ion mass spectra and the development of a predictive model for 13C chemical shifts in flavonoids. At present, Dr. March is carrying out an investigation of volatile compounds formed by Ash trees in response to an attack by the Emerald Ash Borer. These researches are supported by the Natural Sciences and Engineering Research Council of Canada (Discovery Grants Program), the Canada Foundation for Innovation, the Ontario Research and Development Challenge Fund, Ontario Ministry of Natural Resources, and Trent University. Dr. March has enjoyed longterm collaborations with Professor John Todd, with colleagues at l’Université de Provence and l’Université Pierre et Marie Curie (France), and with colleagues in Padova (Italy).

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John F.J. Todd, BSc, PhD, CChem, FRSC, CEng, FInstMC, is currently Emeritus Professor of Mass Spectroscopy at the University of Kent, Canterbury, U.K. He obtained his Class I Honours BSc degree in Chemistry in 1959 from the University of Leeds, from whence he also gained his PhD degree and was awarded the J.B. Cohen Prize in 1963; he was a member of the radiation chemistry group led by the late Professor F.S. (later Lord) Dainton, FRS. From 1963 to 1965, he was a Fulbright Research Scholar and Post-Doctoral Research Fellow in Chemistry with the late Professor Richard Wolfgang at Yale University. In 1965, he was one of the first faculty members appointed to the then new University of Kent at Canterbury, U.K. John and Mavis Todd have been married for 46 years and have three sons: John (Andrew), Eric, and Richard, two daughters-in-law Dorota and Marie, and six grandchildren, Alice, Max, Maja, Luke, Daniel, and Lara. Professor Todd’s research interests, spanning some 44 years, have encompassed positive and negative ion mass spectral fragmentation studies, gas discharge chemistry, ion mobility spectroscopy, analytical chemistry, and ion trap mass spectrometry. His work on 3D quadrupole (Paul) ion traps commenced in 1968, when he first developed the “Quistor/Quadrupole” instrument for the characterization of the behavior of ions confined in radiofrequency electric fields and as a vehicle for the study of gasphase ion chemistry. As a consultant to Finnigan MAT during the 1980s and 1990s, he was a member of the original team that developed the first commercial ion trap mass spectrometer. In another consultancy role, Professor Todd is involved currently with one of the most extended single mass spectrometric investigations ever undertaken: the use of an ion trap mass spectrometer for the isotope ratio measurement of  cometary material as part of the “Rosetta” project (launched 2004, scheduled arrival at its target comet in 2014). Professor Todd has published and/or co-authored some 116 scientific papers and over 118 conference contributions, concentrating mainly on various aspects of mass spectrometry. With Professor Dennis Price, he co-edited four volumes of Dynamic Mass Spectrometry and he edited Advances in Mass Spectrometry 1985 (which contained the proceedings of the 10th International Mass Spectrometry Conference, Swansea, at which he was also a plenary lecturer). In addition, he was an editor of the International Journal of Mass Spectrometry and Ion Processes from 1985 to 1998, has served on the Editorial Boards of Organic Mass Spectrometry/Journal of Mass Spectrometry and Rapid Communications in Mass Spectrometry, and is currently a member of the Board for the European Journal of Mass Spectrometry. With Dr. Raymond E. March, Dr. Todd co-edited three volumes entitled Practical Aspects of Ion Trap Mass Spectrometry, published by CRC Press in 1995. In addition, Dr. Todd was a co-author with Dr. Raymond E. March and Dr. Richard J. Hughes of Quadrupole Storage Mass Spectrometry, published by Wiley in 1989; a second edition of Quadrupole Storage Mass Spectrometry, co-authored by Dr. Todd and Dr. Raymond E. March was published in 2005. Volume IV in the series Practical Aspects of Trapped Ion Mass Spectrometry is in press.

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Professor Todd is a Chartered Chemist and a Chartered Engineer, and has served terms as Chairman and as Treasurer of the British Mass Spectrometry Society. In 1988, he was a Canadian Industries Limited Distinguished Visiting Lecturer at Trent University, Peterborough, Ontario. In 1997, Dr. Todd was awarded the Thomson Gold Medal by the International Mass Spectrometry Society for “outstanding contributions to mass spectrometry,” and in 2006 he was awarded the Aston Medal by the British Mass Spectrometry Society, of which he is also a Life Member. In 2008, he was accorded Honorary Life Membership of the Royal Society of Chemistry. Outside the immediate confines of his academic work, Professor Todd was appointed as Master of Rutherford College, University of Kent (1975–1985), and as the first Chairman of the newly created Canterbury and Thanet Health Authority (UK National Health Service) between 1982 and 1986. During the period 1995–2006 he was the founding Chairman of the newly established Board of Governors of St Edmund’s School Canterbury, and until August 2007 he was a Governor of Canterbury Christ Church University; he was admitted as an Honorary Fellow of Canterbury Christ Church University in 2008. From 1979 to 1989, Professor Todd was Chairman of the Mass Spectrometry Sub-Committee, Commission I.5 of the International Union of Pure and Applied Chemistry (IUPAC), and between 1995 and 2007 he was Chairman of the Management Advisory Panel for the EPSRC National Mass Spectrometry Service Centre, based at the University of Wales Swansea. He has enjoyed long-term collaborations with co-editor Professor Raymond March, with colleagues at Finnigan MAT in the United Kingdom and the United States, and with groups in Nice (France) and Padova and Torino (Italy).

Contributors Alberto Berton CNR-ISTM Corso Stati Uniti 4 Padova, Italy

Michael Drewsen Department of Physics and Astronomy University of Aarhus Aarhus, Denmark

Paola Bocchini Department of Chemistry ‘G. Ciamician’ University of Bologna Bologna, Italy

Gary A. Eiceman Department of Chemistry and Biochemistry New Mexico State University Las Cruces, New Mexico

Francesco L. Brancia Shimadzu Research Laboratory (Europe) Manchester, United Kingdom

Matthew W. Forbes Department of Chemistry University of Toronto Toronto, Ontario, Canada

Jennifer S. Brodbelt Department of Chemistry and Biochemistry University of Texas at Austin Austin, Texas Joseph E. Chipuk Department of Chemistry and Biochemistry University of Texas at Austin Austin, Texas Joshua J. Coon Department of Chemistry and Biomolecular Chemistry University of Wisconsin Madison, Wisconsin Helen J. Cooper School of Biosciences University of Birmingham Edgbaston, Birmingham, United Kingdom

Jennifer M. Froelich Department of Chemistry Michigan State University East Lansing, Michigan Guido C. Galletti Department of Chemistry ‘G. Ciamician’ University of Bologna Bologna, Italy Timothy J. Garrett Department of Medicine University of Florida Gainesville, Florida John E. George III Varian Inc., Scientific Instruments Walnut Creek, California Klaus Højbjerre Department of Physics and Astronomy University of Aarhus Aarhus, Denmark xxix

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Rebecca A. Jockusch Department of Chemistry University of Toronto Toronto, Ontario, Canada Jian Liu Department of Chemistry Purdue University West Lafayette, Indiana Yali Lu Department of Chemistry Michigan State University East Lansing, Michigan Graeme C. McAlister Department of Chemistry and Biomolecular Chemistry University of Wisconsin Madison, Wisconsin Scott A. McLuckey Department of Chemistry Purdue University West Lafayette, Indiana Joel H. Parks The Rowland Institute at Harvard Cambridge, Massachusetts Francesca Pinelli Department of Chemistry ‘G. Ciamician’ University of Bologna Bologna, Italy Benoît Plet European Institute of Biology and Chemistry University of Bordeaux Pessac, France Romina Pozzi Department of Chemistry ‘G. Ciamician’ University of Bologna Bologna, Italy

Contributors

Luca Raveane CNR-ISTM Corso Stati Uniti 4 Padova, Italy Gavin E. Reid Department of Chemistry, Biochemistry and Molecular Biology Michigan State University East Lansing, Michigan Jean-Marie Schmitter European Institute of Biology and Chemistry University of Bordeaux Pessac, France James H. Scrivens Department of Biological Sciences University of Warwick Coventry, United Kingdom Peter Frøhlich Staanum Department of Physics and Astronomy University of Aarhus Aarhus, Denmark John A. Stone Department of Chemistry Queens University Kingston, Ontario, Canada Francis O. Talbot Department of Chemistry University of Toronto Toronto, Ontario, Canada Konstantinos Thalassinos Department of Biological Sciences University of Warwick Coventry, United Kingdom

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Pietro Traldi CNR-ISTM Corso Stati Uniti 4 Padova, Italy Fernande Vedel Physique des interactions ioniques et moléculaires (PIIM) Université de Provence Marseille, France

Mingda Wang Varian Inc., Scientific Instruments Walnut Creek, California Richard A. Yost Department of Chemistry University of Florida Gainesville, Florida

Part I Ion Reactions

Reactions in 1 Ion/Ion Electrodynamic Ion Traps Jian Liu and Scott A. McLuckey Contents 1.1 Introduction.........................................................................................................3 1.2 Tools for the Study of Ion/Ion Reactions............................................................4 1.2.1 Ion/Ion Reactions in Three-Dimensional (3D) Quadrupole Ion Traps..............................................................................5 1.2.2 Ion/Ion Reactions in Linear Ion Traps (LITs).........................................9 1.2.3 Ion/Ion Reactions in Hybrid Instruments.............................................13 1.3 Methodologies/Applications..............................................................................15 1.3.1 Charge State Manipulation: Proton Transfer........................................15 1.3.1.1 Macromolecule Mixture Analysis..........................................15 1.3.1.2 Precursor Ion Charge State Manipulation..............................16 1.3.1.3 Simplification of Product Ion Mass Spectra..........................17 1.3.2 Charge Inversion...................................................................................19 1.3.3 Metal–Ion Transfer................................................................................19 1.3.4 Electron Transfer Dissociation (ETD)..................................................21 1.4 Conclusions....................................................................................................... 24 References...................................................................................................................25

1.1  INTRODUCTION Interactions between gas-phase ions of opposite polarities occur commonly in various environments such as the atmosphere, plasmas, flames [1–4], etc. It has been more than a century since the first study of the interaction between oppositely-charged ions, which can be dated back to the work by Thomson and Rutherford [5]. However, the study of ion/ion reactions can be challenging particularly when the reactions take place between singly-charged cations and anions, as was the case in the majority of the early studies, because the products are neutral species and, therefore, difficult to analyze and detect. With the advent of electrospray ionization (ESI) [6–9] and its propensity for producing multiply-charged ions from high mass molecules, attention has been directed to the reactions between oppositely-charged ions involving multiply-charged ions, which produce charged products readily amenable to study by mass spectrometry. Consequently, a rapidly-growing range of reaction phenomena are being observed in the ion/ion reactions of multiply-charged ions, which is permitting new insights to be drawn regarding ion/ion reaction thermodynamics and dynamics. While ion/ion 3

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reactions involving large multiply-charged ions are not important in plasmas or flames, for example, they are enabling an expanding array of new analytical applications, particularly in bioanalysis. Although ion/ion reactions can be implemented readily under various ­conditions, including near atmospheric pressure [10–15], ion/ion reactions performed in electrodynamic ion traps afford the opportunity for selective ion manipulation due to the mass/charge-dependent frequencies of motions executed by stored ions. Therefore, ion traps allow for the study of ion/ion reactions within the context of tandem mass spectrometry (MSn) experiments. As a result, many ion/ion reaction studies have been undertaken in electrodynamic ion trap-based instruments. Several reviews [16–18] of ion/ion reactions involving multiply-charged ions have been published, that focus on aspects of instrumentation, applications, reaction phenomena, and fundamentals including thermodynamics and kinetics. Rather than providing a comprehensive discussion of all aspects related to ion/ion chemistry, this chapter aims primarily to provide a brief description of the instrumentations, methodologies, and applications of ion/ion reactions in ion traps, especially within the context of biomolecule analysis, with particular emphasis on developments since the publication of recent reviews.

1.2 TOOLS FOR THE STUDY OF ION/ION REACTIONS Fundamental requirements for any tool intended for ion/ion reaction studies are the ability to generate ions of opposite polarities within a single experiment, and to furnish an interaction environment delivering good spatial and temporal overlap for the oppositely-charged ion populations. The environment for the ion/ion interaction can be created either outside or inside a mass spectrometer. The first ion/ion reactions involving multiply-charged ions, for example, were demonstrated at near atmospheric pressure (ca 2 Torr) using a Y-tube flow reactor [10,11], which admit, into separate inlet arms of the reactor, ions of opposite polarities produced by two ion sources, for example, ESI, and discharge sources. The ion/ion reactions took place once the two ion streams merged in the outlet arm of the reactor, which was coupled to the interface of the mass spectrometer, before sampling into the instrument. Implementation of ion/ion reactions external to the mass spectrometer separates physically the ionization process and ion/ion reactions from the mass analysis step. Advantages derived from this separation include the simplicity with which such ion/ion reactors can be adapted to any mass spectrometer coupled with ESI, independent optimization of mass analysis, and virtually no limits are imposed by the characteristics of the mass analyzer on the kinds of ions that can be used as reactants. However, reaction conditions can be difficult to define in reactors operating at near atmospheric pressure due to the existence of a complicated reaction environment, where a mixture of ions, solvent vapors, and atmospheric gases are present in the reaction region. This situation can lead to ambiguities in the determination of mechanisms that give rise to products in some cases. Moreover, implementing ion/ ion reactions outside a mass spectrometer does not allow for a true tandem mass spectrometric experiment to be performed involving an ion/ion reaction between mass analysis stages. Many of the drawbacks associated with the implementation of

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ion/ion reactions outside a mass spectrometer can be overcome by using an electrodynamic ion trap as a reaction vessel, at the cost of somewhat greater experimental complexity.

1.2.1 Ion/Ion Reactions in Three-Dimensional (3D) Quadrupole Ion Traps The majority of the early studies of ion/ion reactions under low pressure (ca 1 mTorr) conditions were performed with three-dimensional (3D) ion traps (that is, conventional Paul traps), which store ions in three dimensions by a radio-frequency (RF) voltage applied to a central ring electrode sandwiched between two end-cap electrodes. The 3D ion trap is inherently compatible with the study of ion/ion reactions due to its unique ability to store simultaneously ions of both polarities in overlapping regions of space [19,20]. The trapped ion assumes a characteristic set of m/z-dependent frequencies of motions in the oscillating quadrupole field of the ion trap, which allows ready manipulation of ions of specific massto-charge ratios for ion isolation and activation, both of which are common elements in a tandem mass spectrometric experiment. The ‘tandem-in-time’ nature of the ion trap MSn experiment [21,22] provides well-defined conditions for ion/ion reactions and is particularly useful in the determination of ion genealogy. Furthermore, the use of a bath gas, such as helium at ca 1 mTorr in the ion trap, intended originally to cool the ions translationally into the center of the trap to improve the mass resolution for the mass analysis [23], also improves ion/ion reaction efficiencies by maximizing the spatial overlap and minimizing the translational energies of the two ion clouds [24]. While the ion trap is particularly well-suited to serve as a reaction vessel for ion/ion reactions, it places constraints on the range of reactions that can be studied. For example, all of the reactant and product ions must fall within the limited range of m/z-values that can be stored simultaneously in an ion trap. The normal operation of the ion trap places a lower limit to the mass-to-charge value for ion storage, also known as low mass cut-off (LMCO) [25] of the ion trap, which is defined sharply by the operating RF (that is, RF frequency and amplitude) and ion trap dimensions. Any ion having an ­m/z-value less than the LMCO assumes an unstable trajectory and will be ejected from the ion trap. In the absence of a DC field, all ions having m/z-values greater than the LMCO lie within the region of ion stability of the ion trap. However, ions of different mass-to-charge values experience different trapping potentials in the ion trap, as approximated by the so-called pseudo-potential trapping well ( Dz ) [25], which is defined also by the amplitude and frequency of the RF operating voltage, and the ion trap dimensions. The magnitude of the pseudo-potential trapping well is approximately inversely proportional to the mass-tocharge ratio at qz  20 kDa) is characterized by low fragmentation efficiency. Abundant peaks corresponding to chargereduced species but few backbone product ions are observed. Electron capture cleaves

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the peptide backbone but fails to disrupt non-covalent bonds. Similar behavior is seen for smaller tightly-folded species. Activated ion ECD [75,84,85], in which ions are heated prior to, during, or after ECD circumvents this problem. As a result of heating, the ions are unfolded enabling the sequence fragments to dissociate. Activation of ions can be achieved by infrared irradiation, blackbody irradiation, or collisional activation using a nitrogen gas pulse. An alternative approach is plasma ECD [86], in which electrons (0.1−15 eV) are collided with pulsed nitrogen gas prior to the trapping of ions in the ICR cell. The induced plasma conditions result in significant increase in ECD efficiency. A single plasma ECD mass spectrum of carbonic anhydrase (ca 29 kDa) showed peaks corresponding to cleavage of 183/253 N–Cα bonds cf 116/258 by activated ion ECD.

5.3 HYBRID FOURIER TRANSFORM ION CYCLOTRON RESONANCE (FT-ICR) INSTRUMENTS Since 2000, the field has moved increasingly toward hybrid FT-ICR instruments in which the FT-ICR is interfaced with a front-end mass analyzer. The groups of Marshall [46,47] and Smith [48,49] introduced the quadrupole-FT-ICR. That configuration is available commercially. The hybrid linear ion trap FT-ICR [87] was introduced commercially in 2003. Hybrid instruments offer greater versatility in terms of mass-selective external accumulation with the associated increase in sensitivity and dynamic range.

5.3.1 Quadrupole-Fourier Transform Ion Cyclotron Resonance (FT-ICR) The benefits of the accumulation of ions external to the ICR cell are described above. As ion detection and accumulation are separated physically, one packet of ions is being detected whilst the next packet is being accumulated. The duty cycle, that is, the fraction of time that ions are accumulated for detection, can therefore approach 100%. In addition, external accumulation of ions results in enhanced signal-to-noise ratio and mass resolving power [13]. A factor which limits the maximum achievable duty cycle is the time taken to purge the external trap of ions. Smith and co-workers [48] introduced a 10-cm long segmented accumulation quadrupole that could be purged completely of ions in 400 µs. Marshall and co-workers introduced an alternative approach, in which a direct current (DC) voltage is applied to angled wires positioned between adjacent rods of the accumulation octopole [88]. Further benefits can be realized by the implementation of mass-selective external accumulation. The dynamic range and sensitivity of the instrument are improved. Mass-selective external accumulation can be achieved by interfacing a quadrupole mass filter with the FT-ICR mass spectrometer. The quadrupole can be operated either in RF/DC mass filtering mode, in which one m/z region traverses the quadrupole, or in RF-only resonant dipolar excitation mode. The latter allows selective removal of multiple m/z peaks. For example, Smith and co-workers showed that this mode could be applied to remove the [M + 16H]16 + and [M + 14H]14 + ions of myoglobin from the charge-state envelope + 13 through + 18 [49].

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5.3.2 Linear Ion Trap-Fourier Transform Ion Cyclotron Resonance (FT-ICR) An alternative approach was introduced by Hunt and co-workers [87]. Those researchers coupled a linear quadrupole ion trap, consisting of four rods of hyberbolic crosssection, with an FT-ICR mass spectrometer. The linear ion trap allows accumulation of larger populations of ions than does a standard three-dimensional (3D) ion trap. The hybrid linear ion trap-FT-ICR instrument enables simultaneous detection in both mass analyzers. This aspect is particularly advantageous for ‘data-dependent’ MS/ MS methods used in proteomics, and is discussed further below. The commercial version of this instrument features automated gain control that accumulates a fixed number of charges before delivery to the ICR cell. Because the ‘ideal’ ion density is attained in the cell, space-charge effects resulting in loss of mass resolution and mass accuracy, are eliminated.

5.4 APPLICATIONS OF FOURIER TRANSFORM ION CYCLOTRON RESONANCE (FT-ICR) IN PROTEOMICS Proteomics [89,90] is the study of the entire complement of proteins expressed by a cell or tissue type. The focus of a proteomics experiment, for example, might be identification of proteins that differ according to growth conditions or according to disease state. The aims are to identify and to characterize the maximum number of significant ­proteins. Proteomics experiments can be described as ‘bottom-up,’ in which proteins are digested with a protease and the resulting peptides are analyzed by mass spectrometry. Alternatively, a “top-down” approach, in which intact proteins are characterized, can be applied [53]. FT-ICR has found applications in both approaches, as discussed below.

5.4.1  ‘Bottom-Up’ Approaches ‘Bottom-up’ proteomics involves digestion of proteins with a protease, usually trypsin, and subsequent mass spectrometric analysis of the resulting peptides. The masses of the tryptic peptides are characteristic of the parent protein. Either a peptide mass fingerprinting approach can be employed, or peptide sequencing by MS/MS can be performed. Peptide sequencing involves generally separation of the peptide mixture by on-line LC. As the peptides elute, they are ionized by electrospray and analyzed by MS/MS. In both the peptide mass fingerprinting and peptide sequencing methods, the data are searched against a protein database. 5.4.1.1  Peptide mass fingerprinting In proteomics, peptide mass fingerprinting of the peptide mixture is undertaken frequently by ionization by MALDI followed by time-of-flight mass analysis. However, the high mass accuracy and resolving power of FT-ICR mass spectrometry can be exploited for this approach. It is possible to resolve virtually all peptide isobars differing by up to two amino acids, even those differing by the smallest mass difference of 3.4 mDa. Resolution of two peptides differing by 11 mDa in a complex mixture of 1000s of peptides has been demonstrated [91]. Clearly, isomers require MS/MS

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while, in the case of leucine/isoleucine, HECD is required. Further confidence in the accuracy of mass measurement can be gained through use of a dual electrospray source [92,93], in which an internal mass calibrant is introduced via a separate electrospray emitter. Consequently, space-charge effects in the ICR cell are mitigated without the inherent problem of electrospray ion suppression. Peptide mass fingerprinting can be performed by use of MALDI-FT-ICR [94,95]. For example, Przybylski and co-workers applied MALDI-FT-ICR to the proteomic analysis of cryoglobulins from a hepatitis C patient [96], and to alveolar proteomics associated with proteinosis and cystic fibrosis [97]. Alternatively, LC can be coupled with ESI FT-ICR for peptide mass fingerprinting [94]. Among other applications, LC coupled with ESI-FT-ICR has been used in the proteomic analysis of Escherichia coli [98], the proteomic analysis of amniotic fluid [99], the identification of brain natriuritic peptide (BNP-32) in plasma following heart failure [100], and in the molecular differentiation of ischemic and valvular heart disease [101]. An alternative approach, which exploits the high mass accuracy of FT-ICR, is the use of accurate mass tags (AMT) [17–19]. The approach involves initial creation of a set of AMTs which act as biomarkers for their parent proteins. Potential mass tags are generated by LC along with MS/MS performed on a conventional ion trap instrument, and then validated by FT-ICR and LC retention time. This initial procedure is relatively time-consuming but, once the AMTs are generated, high-throughput experiments can be performed subsequently. The approach has been applied to the global analysis of the Deinococcus radiodurans proteome [19], and proteomics analysis of breast carcinoma cells [102]. 5.4.1.2  Peptide Sequencing Methods incorporating FT-ICR MS/MS have been applied also to bottom-up proteomic analyes. Hakansson et al. [66] applied ESI FT-ICR and IRMPD MS/MS to the analysis of glycoproteins isolated from human cerebrospinal fluid. Brock and co-workers [103] combined MALDI FT-ICR with SORI-CID. The throughput of this approach is hampered by the timescales associated with SORI-CID. Laskin and co-workers [104] compared approaches utilizing SORI-CID and SID coupled to ESI. The protein identification scores were comparable for the two techniques. SID has the advantage that no pump-down delay is needed and, therefore, more cycles of MS/ MS can be completed. 5.4.1.2.1  Liquid Chromatography (LC) Tandem Mass Spectrometry (MS/MS) The majority of peptide-sequencing proteomic experiments involve coupling of LC with MS/MS. Protein spots may be excised from a two-dimensional (2-D) gel and digested prior to reversed-phase LC-MS/MS. Alternatively, a whole cell lysate may be digested and separated by 1 or 2-D (strong cation exchange and reversed phase) ­on-line LC followed by MS/MS; this approach is known as the shotgun approach [105]. The hybrid linear ion trap FT-ICR instrument allows simultaneous collection of MS data in the ICR cell and CID MS/MS data in the linear ion trap [106]. A common workflow involves one FT-ICR survey MS scan and linear ion trap CID scans of the three most abundant ions. Dynamic exclusion prevents re-analysis of precursor ions. The ­timescale for an FT-ICR scan is ca 1s (100,000 resolution at m/z 400) whereas a linear ion trap CID event takes ca 300 ms. This method is demonstrated in Figure 5.9.

141

Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (a) #1345 RT: 29.86 512.2562

714.8323

489.5394 432.2817

707.6076

735.4080

524.9059 674.3078 570.7399 625.3184 400

500

600

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700 m/z

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(b) 513.16

#1346 RT: 29.87 Full ms2 524.91

657.30 488.56 648.26

383.28 374.38 200

300

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730.28 700

800

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(c) 974.16 #1347 RT: 29.88 Full ms2 625.32

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276.05 231.13 200

551.97 606.90 391.13 504.10 616.25 431.12

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(d)

600 m/z

956.15 819.13

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401.06 335.98 300

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606.00 547.98 530.07 500

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676.78

Full ms2 707.61

200

800

777.83

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#1348 RT: 29.89

859.12

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FIGURE 5.9  ‘Snapshot’ of an LC CID MS/MS analysis of a tryptic digest of a mixture of six proteins (bovine serum albumin, transferrin, cytochrome c, lysozyme, alcohol dehydrogenase, and β-galactosidase). RT = retention time. (a) FT-ICR survey scan (#1345); (b) Linear ion trap CID MS/MS of precursor m/z 524.9 (#1346); (c) Linear ion trap CID MS/MS of precursor m/z 625.3 (#1347); and (d) Linear ion trap CID MS/MS of precursor m/z 707.6 (#1348).

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Figure 5.9 shows a snapshot of an LC CID MS/MS analysis of a tryptic digest of a standard six-protein mixture. The top mass spectrum (scan # 1345 in this experiment) is an FT-ICR survey scan. In the subsequent scan (# 1346), CID MS/MS of the precursor ion m/z 524.9 is performed in the linear ion trap. That precursor ion is the most abundant ion in the survey scan that has not been subjected previously to MS/MS, that is, is not on the exclusion list. Scan # 1347 is the CID mass spectrum of precursor m/z 625.3, the second most abundant ion, not on the exclusion list, in the survey scan. The sequence ends with CID of precursor m/z 707.6, the third most abundant ion, not on the exclusion list, in the survey scan. The subsequent scan (not shown) is an FT-ICR survey scan. An alternative workflow favored by some researchers is one FT-ICR survey MS scan followed by CID in the linear ion trap of the 10 most-abundant ions [107]. These ‘parallel-processing’ approaches have been applied to a diverse range of studies including analysis of the chicken egg white proteome [108], the low molecular weight proteome of Halobacterium salinarum [109], the endocervical mucas proteome [110], sumoylation in Saccharomyces cerevisiae [111], and the tear fluid proteome [112]. It is also possible to combine on-line LC with ECD MS/MS. This approach was applied to the analysis of the protein Fc-ROR2 that was isolated from chondrocytes and digested with trypsin [113]. Analysis by LC ECD MS/MS cannot be undertaken in a parallel manner: ECD must take place in the ICR cell. The previous survey scan must, therefore, be completed prior to ECD. Consequently, the duty cycle is reduced. A further disadvantage of this approach is the inherent inefficiency of ECD (see above). It is necessary to accumulate more precursor ions for ECD, with a concomitant increase in experiment time. The accumulation time is of the order of seconds rather than the milliseconds required for accumulation for CID. Nevertheless, studies have shown that ECD results in longer peptide sequence tags than does CID, thus improving confidence in peptide assignment [114]. Approaches which combine LC with ECD and CID have been developed also and are discussed further below [115–118]. 5.4.1.2.2  Post-Translational Modification (PTM) Analysis Post-translational modification (PTM) of proteins plays a vital role in many biological processes. For example, phosphorylation is a key event in many signaling cascades, ubiquitination targets proteins for degradation, and glycosylation is involved in cell–cell recognition. Identifying and characterizing modified proteins is a major goal in proteomics. The ease with which this can be undertaken depends largely on the lability of the modification and its stoichiometry. ‘Parallel-processing’ methods in which high resolution, high mass accuracy FT-ICR survey scans are combined with lower specification CID scans (see above) have been applied to the study of ubiquitination and sumoylation of proteins [119–121]. Both of these modifications are relatively stable. ‘Parallel-processing’ methods have been applied also to global analyzes of the phosphoproteome [122], and hundreds of phosphoproteins have been identified. The Ascore algorithm, developed by Gygi and co-workers [123], can be applied to these data to determine site localization confidence. Phosphorylation of serine and threonine (but less so phosphotyrosine) are particularly labile modifications. CID of peptides containing either phosphoserine or phosphothreonine tends to result in loss of phosphoric acid (H3PO4,−98 Da) at the expense of peptide backbone

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product ions. Observation of a peak corresponding to the neutral loss confirms the presence of the modification but often precludes its localization. Global phopshoproteome analyzes can be performed also by use of electron transfer dissociation (ETD) [124,125]. These analyzes utilized either 3D quadrupolar ion trap or linear ion trap instruments and are beyond the scope of this chapter. Targeted ECD approaches have been developed that exploit the advantages of ECD, in particular the retention of labile modifications on peptide backbone fragments, while minimizing the disadvantage of time scale. Experiments are performed on a hybrid linear ion trap FT-ICR mass spectrometer. Neutral losstriggered ECD (NL-ECD) [118] uses observation of a neutral loss as a trigger for an ECD event. The most abundant multiply-charged ion identified in the FT-ICR survey scan is subjected to CID in the linear ion trap in the subsequent scan. When a neutral loss peak, for example, H3PO4, −98 Da, is observed, the following scan will be ECD of the precursor ion (not the neutral loss peak). An alternative approach involving separate LC analyses has been developed. The first LC experiment involves CID of the eluting peptides. The purpose of this analysis is phosphopeptide discovery based on mass of the precursor and any sequence product ions observed. The m/z ratios of the putative phosphopeptides are added to an inclusion list and an LC-ECD analysis is performed. In this experiment, only those ions on the inclusion list are interrogated by ECD. This approach has been applied to the analysis of the protein Sprouty2 [126]. Fourteen sites of phosphorylation were identified of which 11 were novel. Zubarev and co-workers utilized a combined ECD CID approach for the bottom-up analysis of phosphorylation in human α-casein [127]. The method involved an FT-ICR survey scan followed by ECD and CID of the two most abundant precursor ions. These researchers identified a site of phosphorylation that, although known in the bovine form, had not been reported previously for human α-casein.

5.4.2  ‘Top-Down’ Approaches FT-ICR mass spectrometry has great potential for ‘top-down’ proteomics [128], that is, characterization of intact proteins. The high resolution and mass accuracy are well-suited to the analysis of large biomolecules. Moreover, these features allow direct and accurate mass measurement of multiply-charged product ions, that is, in top-down MS/MS. To date, top-down MS/MS has been applied to characterization of proteins and large polypeptides up to 60 kDa [129]. The top-down approach offers some advantages over the bottom-up approach for protein characterization. Because intact proteins are analyzed, 100% sequence coverage is achieved. The method is, therefore, particularly suited to PTM analysis. The highest mass molecule for which unit resolution was achieved was 112,508 Da [20] by use of a 9.4 T instrument. As FT-ICR magnetic field strength increases, unit resolution should be achieved for even higher mass molecules. Unit resolution enables modifications such as disulfide bridge formation (−2 Da) or deamination ( + 1 Da) to be identified. A disadvantage of the bottom-up approach is that any connectivity between modifications or mutations in the protein sequence is lost. For example, a protein with

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mutation at amino acid Xxx may be phosphorylated uniquely at amino acid Zzz. Any such information is lost following proteolytic digestion. For example, Ge et al. [130], performed top-down analyses of proteins isolated from Mycobacterium tuberculosis. One protein assignment, which was based on the mass of the intact species, was found subsequently to be erroneous based on ECD MS/MS data. The MS/MS results showed that, in fact, the species was a truncated version of a different protein. It would not have been possible to demonstrate this distinction using a bottom-up approach. A potential drawback for top-down analyses is that, as the molecular weight of a protein increases, it becomes less likely that the monoisotopic peak will be observed. For proteins ≥ 15 kDa, the monoisotopic peak is  0.9 and az between –0.3 and –0.8, the kinetic energy imparted to the ion by the field is so high that ion behavior in the proximity of the stability boundary differs from that expected on the basis of theoretical calculations due to resonant excitation/ejection. For instance, in the case of 3 (Figure 12.10), ions were ejected due to trajectory instability at the working point az = –0.500 and qz = 0.938, calculated from Equations 12.2 and 12.1, respectively. Thus the working point (0.500, 0.938) defines this point on the experimentally-determined βz = 1 boundary of the stability diagram. The qz -value of the computed βz = 1 boundary of the stability diagram at az = –0.500 is 0.958. Thus, at az = –0.500, the difference in qz -values between the experimentally-determined βz = 1 boundary of the stability diagram and the computed βz = 1 boundary of the stability diagram is 0.020. When 1 is analyzed (Figure 12.8), ions were ejected due to trajectory instability at the working point az = –0.520 and qz = 0.900, calculated again from Equations 12.2 and 12.1, respectively. Thus the working point (0.520, 0.902) defines this point on the experimentally-determined βz = 1 boundary of the stability diagram. The qz -value of the computed βz = 1 boundary of the stability diagram at az = –0.520 is 0.966. Thus, at az = –0.520, the difference in qz -values between the experimentallydetermined βz = 1 boundary of the stability diagram and the computed βz = 1 boundary of the stability diagram is 0.064. In fact, regardless of the duration of the cooling time, the application of a DC component brings ions into a region of the ion trap in which the RF field is larger and the ions are ­accelerated to higher kinetic energies. Because of this effect, ions undergo energetic collisions with the background gas and depletion of the monoisotopic ion signal intensity is observed due to unwanted fragmentation. Closer examination of the product ion mass spectra indicates the presence of product ions produced by collisions with the buffer gas. The results suggest that variation of the waveform duty cycle, which is achieved at the software level by entering different values in the scan table, can result in a relatively simple approach for generating BAD without the necessity of an additional power supply. The behavior of 1 can be explained considering the different charge state of the ions used as probes. Ion 1, which displays the largest discrepancy between the

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Boundary-Activated Dissociation (BAD) in a Digital Ion Trap (DIT)

computed βz = 1 boundary and the experimentally-determined βz = 1 boundary, is a doubly-charged species, with the m/z-value close to those for 2 and 3. Its interaction with the trapping field is consequently stronger: in other words, the doubly-protonated species is able to increase its kinetic energy at (az, qz)-values that are lower than those necessary to excite similarly 2 and 3 to achieve a comparable enhancement of kinetic energy. If this hypothesis is true, the loss of ion 1 in the right-hand side of the stability diagram is not due to its ejection from the ion trap and/or its discharge on the trap walls, rather it is caused by the activation of decomposition channels due to the increase of kinetic energy and effective collisions with helium. To verify this hypothesis, some experiments were performed by using different (az, qz)-values, corresponding to the points (a)–(d) shown in Figure 12.13. The mass spectra obtained under these conditions are shown in Figure 12.14. Singly-charged ions, at m/z-values higher than the doubly-charged precursor ion, are observed, providing evidence on the occurrence of boundary-activated chargeseparation dissociations. Among all the various experimental conditions examined, those leading to the best result (with respect to signal-to-noise ratio) correspond to point (b), which is reasonable considering the larger qz -range available that permits the storage of high-mass ions. However, when loci (discussed below) are drawn from the origin through the working points (a)–(d), it is found that the lengths of the loci lying within the stability diagram decrease in the order (a)–(d). Inspection of Figure 12.13 yields the qz-values for the intersection of these loci with the βz = 0 boundary from which the highest m/z-value for product ions remaining confined in the DIT can be calculated. The product ion mass/charge ratio reaches its greatest value at m/z 1730 for (a); m/z 1200 for (b); m/z 765 for (c); and m/z 672 for (d). As shown by the values for the high-mass/charge limit for points (a)–(d), m/z 555 is in no danger of being ejected and so it is not surprising that its intensity is sensibly constant. For the 0.2 0.1 0 –0.1 –0.2

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8 a 0.9

1

11

qz

b

az

–0.3 –0.4 –0.5

c d

–0.6 –0.7 –0.8

FIGURE 12.13  Selected working points employed to perform BAD experiments on [M+2H]2+ ions of bradykinin; (a) (–0.140, 0.750); (b) (–0.260, 0.815); (c) (–0.450, 0.895); and (d) (–0.570, 0.926).

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Normalized accumulated intensity

(a) 100 95 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5

[M+2H]2+ b5

515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559

Mass/charge

(b) Normalized accumulated intensity

100 95 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5

b5

515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559

Mass/charge

Normalized accumulated intensity

(c) 100 95 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5

[M+2H]2+

b5

515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559

Mass/charge

Normalized accumulated intensity

(d) 100 95 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5

[M+2H]2+

b5

515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559

Mass/charge

FIGURE 12.14  Product ion mass spectra obtained using BAD of [M+2H]2+ of ­bradykinin at the following selected working points identified in Figure 12.13: (a) (–0.140, 0.750); (b) (–0.260, 0.815); (c) (–0.450, 0.895); and (d) (–0.570, 0.926).

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point (d), the loss of some high-mass ions is expected. The locus of (az, qz)-values for all product ions is a straight line connecting point (d) (in Figure 12.13) to the origin of the stability diagram; it is seen that part of this locus falls outside the βz = 0 boundary of the stability diagram such that the trajectories of a range of product ions are rendered unstable and the ions are lost. These data indicate that BAD implemented in the DIT represents a realistic alternative for MS/MS experiments.

12.3  CONCLUSION Among all non-resonant activation techniques, BAD has been shown to have unique advantages for the formation of product ions. Due to the necessity to utilize an additional power supply for generating the DC component, such an approach has not been used in any commercial mass spectrometer. Conversely, in the DIT, variation of the duty cycle of the rectangular waveform is controlled at software level and it allows readily introduction of the DC component for BAD experiments.

REFERENCES

1. Fulford, J.E.; Hoa, D-N.; Hughes, R.J.; March, R.E.; Bonner, R.F.; Wong, G.J. Radiofrequency mass selective excitation and resonant ejection of ions in a three-dimensional quadrupole ion trap. J. Vac. Sci. Technol. 1980, 17, 829–835. 2. Louris, J.N.; Cooks, R.G.; Syka, J.E.P.; Kelley, P.E.; Stafford Jr., G.C.; Todd, J.F.J. Instrumentation, applications and energy deposition in quadrupole ion trap MS/MS spectrometry. Anal. Chem. 1987, 59, 1677–1685. 3. Gronowska, J.; Paradisi, C.; Traldi, P.; Vettori, U. A study of relevant parameters in collisional-activation of ions in the ion-trap mass spectrometer. Rapid Commun. Mass Spectrom. 1990, 4, 306–314. 4. Louris, J.N.; Brodbelt, J.E.; Cooks, R.G. Photodissociation in a quadrupole ion trap mass spectrometer using a fiber optic interface. Int. J. Mass Spectrom. Ion Processes 1987, 75, 345–352. 5. Lifshitz, C. Dissociative photoionization in the vacuum UV region with ion trapping. Int. J. Mass Spectrom. Ion Processes 1991, 106, 159–173. 6. McLuckey, S.A.; Goeringer, D.E.; Glish, G.L. Collisional activation with random noise in ion trap mass spectrometry. Anal. Chem. 1992, 64, 1455–1460. 7. Julian, R.K.; Cox, K.; Cooks, R.G. Proc. 40th ASMS Conference on Mass Spectrometry and Allied Topics. Washington, DC, 31 May–5 June 1992, p. 943. 8. Pannell, L.K.; Pu Q.L.; Mason, R.T.; Fales, H.M. Fragment pathway analysis using ­automated tandem mass spectrometry on an ion-trap mass spectrometer. Rapid Commun. Mass Spectrom. 1990, 4, 103–107. 9. Lammert, S.A.; Cooks, R.G. Pulsed axial activation in the ion trap: A new method for performing tandem mass spectroscopy (MS/MS). Rapid Commun. Mass Spectrom. 1992, 6, 528–530. 10. Varian, Walnut Creek, CA, USA, Technical literature. 11. Paradisi, C.; Todd, J.F.J.; Traldi, P.; Vettori, U. Boundary effects and collisional activation in a quadrupole ion trap. Org. Mass Spectrom. 1992, 27, 251–254. 12. Paradisi, C.; Todd, J.F.J.; Vettori, U. Comparison of collisional activation by the ‘boundary effect’ vs. ‘tickle’ excitation in an ion trap mass spectrometer. Org. Mass Spectrom. 1992, 27, 1210–1215.

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13. Traldi, P.; Catinella, S.; March, R.E.; Creaser, S.C. Boundary excitation. In Practical Aspects of Ion Trap Mass Spectrometry, eds. R.E. March and J.F.J. Todd, Vol. 1, Chapter 7, pp. 299–341. CRC Press, Boca Raton, 1995. 14. March, R.E.; Todd J.F.J. Quadrupole Ion Trap Mass Spectrometry. 2nd Edn. John Wiley & Sons, Hoboken, NJ, 2005, pp. 280–290 (references cited therein). 15. Vachet, R.W.; Glish, G.L. Boundary-activated dissociation of peptide ions in a quadrupole ion trap. Anal. Chem. 1998, 70, 340–346. 16. Ding, L.; Sudakov, M.; Kumashiro, S. A simulation study of the digital ion trap mass spectrometer. Int. J. Mass Spectrom. 2002, 221, 117–138. 17. Konenkov, N.V.; Sudakov, M.; Douglas, D.J. Matrix methods for the calculation of stability diagrams in quadrupole mass spectrometry. J. Am. Soc. Mass Spectrom. 2002, 13, 597–613. 18. Berton, A.; Traldi, P.; Ding, L.; Brancia, F.L. Mapping the stability diagram of a digital ion trap (DIT) mass spectrometer by varying the duty cycle of the trapping rectangular waveform. J. Am. Soc. Mass Spectrom. 2008, 19, 620–625.

Study of Ion/ 13 The Molecule Reactions at Ambient Pressure with Ion Mobility Spectrometry and Ion Mobility/Mass Spectrometry Gary A. Eiceman and John A. Stone Contents 13.1 Introduction................................................................................................. 388 13.2 The Ion Mobility Spectrometer and a Mobility Measurement.................... 389 13.2.1 The Profiles of Ion Mobility Spectra Used to obtain Thermodynamic and Kinetic Data................................................ 391 13.2.1.1 Type 1. Equilibrium A + + B = AB + Exists Throughout the Source and Drift Region..................... 393 13.2.1.2 Type 2. A + + B→AB + in the Drift Region................... 393 13.2.1.3 Type 3. A+ and AB + are Formed in the Source Region and Neither A Nor B is Present in the Drift Region........................................................................... 394 13.2.2 Examples Where Thermodynamic and Kinetic Data have been obtained from Ion Mobility Spectra..................................... 394 13.2.2.1 Type 1. Ions in Equilibrium Showing a Single Peak in the Mobility Spectrum.............................................. 395 13.2.2.2 Type 2. Reaction Rate Constant Measurements...........400 13.2.2.3 Type 3. Dissociation of Adduct Ions.............................403 13.2.3 The Kinetics of Thermal Electron Capture and Thermal Electron Detachment.....................................................................406 13.2.3.1 Electron Capture...........................................................406 13.2.3.2 Thermal Electron Detachment......................................409

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13.3 Concluding Remarks................................................................................... 411 References............................................................................................................... 412

13.1  INTRODUCTION In the Prefaces to Volumes 4 and 5 of Practical Aspects of Trapped Ion Mass Spectrometry the Editors have explained that, in defining the scope of these publications, it is considered that “an ion is ‘trapped’ when its residence time within a defined spatial region exceeds that had the motion of the ion not been impeded in some way.” Ion mobility spectrometry (‘IMS’) operated at atmospheric pressure, which falls clearly within this definition, involves the determination of the time taken for the components of a packet of ions to move through a defined distance under the influence of a specified electric field gradient and against the counter current flow of a drift gas at ambient pressure. Ion mobility spectrometers have been utilized for monitoring hazardous or controlled substances in a range of venues on land, in flight, in space, and underwater in submarines, and are ubiquitous at airports for detecting explosives in carry-on articles [1–18]. Such uses have arisen from the pragmatic attractions of these analyzers including ruggedness, small size, and affordability. Measurements by IMS are based on the production and determination of gaseous ions derived from a sample and are made commonly at ambient pressure so vacuum systems and associated pumps are unnecessary [19–22]. These features account for the portability of IMS analyzers and, along with the convenience of use and speed of operation, often make mobility spectrometers the instrument of choice for in-field, routine, measurements. An early term for IMS was plasma chromatography from the presence of a plasma, that is, both positive and negative ions in the ion source, and from the separation of ions in the supporting medium, air, or nitrogen. As with gas or liquid chromatograms, ion mobility spectra alone lack the facility for unequivocal identifications because the relationship of an ion mobility measurement to the structure or identity of an ion is under-developed. Consequently, mass spectrometers were combined with mobility drift tubes early in the development of IMS to provide ion identities through mass analyses. The combination of mobility and mass measurements can also permit the study of reactions between gaseous ions and molecules at ambient pressure in air, or other gases, and the measurement of both kinetic and thermodynamic values. Thermodynamic data that are suitable for tabulation include standard enthalpies, entropies, and free energies and can be regarded as universally applicable for systems at specified temperature when all participants are at thermal equilibrium. Though such data can also be obtained without thermal equilibrium, compensating experiments, or mathematical corrections are required, sometimes creating difficulties in practice and/or interpretation. A chemical system in the gas phase can reach thermal equilibrium, at a defined temperature, when a sufficient number of intermolecular collisions produce a Boltzmann distribution of energies in all modes, electronic, vibrational, rotational, and translational. In measurements made with an ion trap instrument or Fourier Transform Ion Cyclotron Resonance (FT-ICR) spectrometer at low pressure, hot ions must be cooled, commonly with a pulse of buffer

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gas, and time allowed for thermalization, with the number of thermalizing collisions directly proportional to pressure. Such techniques are unnecessary with an ion mobility spectrometer at ambient pressure because each ion experiences more than 1010 collisions per second, mainly with neutral atoms or molecules of the supporting gas atmosphere. When the concentration of a sample compound is 1 ppm by volume, for example, then, on an average, an ion undergoes one collision with a molecule of the sample compound for every million collisions with the molecules of the gas atmosphere. Thus, there are ca 104 ion/sample-molecule collisions per second for possible reactions, under thermalized conditions for well-defined temperatures. Additionally, the residence time of an ion in an ion mobility spectrometer operating at atmospheric pressure is ca 5–50 ms, which allows the study of the interactions of ions with molecules at very low concentrations. A further advantage with IMSbased thermochemical determinations is that the available temperature range, from sub-ambient to more than 500 K, is far greater than that available with many other experimental methods. In spite of the advantages cited above, ion mobility spectrometers operating at atmospheric pressure have been used infrequently to obtain physical chemical data, kinetic and thermodynamic, in the study of ion/molecule chemistry. In this chapter, an overview is given on the type of information obtainable from ion mobility studies at atmospheric pressure and the variety of experimental methods employed in such studies. The data obtained under well-defined conditions agree favorably with those from other more frequently used methods, for example: (i) pulsed high pressure mass spectrometry (PHPMS), which is operated at well-defined temperatures but at pressures ca 200 times lower than IMS; and (ii) FT-ICR and ion trap mass spectrometers, which are operated under vacuum.

13.2 THE ION MOBILITY SPECTROMETER AND A MOBILITY MEASUREMENT An ion mobility spectrometer is a simple device with three essential elements: a source region, a drift region, and a detector. The drift tube usually is cylindrical with an overall length from 5 to 10 cm and an internal diameter from 1 to 5 cm. Metal rings separated by insulating material, for example Teflon®, provide a uniform electrostatic drift field when the source end is at high potential and the detector is essentially at ground potential. The high potential is positive for the detection of positive ions and negative for negative ions. The source region is separated from the drift region, as shown in Figure 13.1, by an ion shutter composed of two closelyspaced sets of interdigitated wires, grids 1 and 2 in Figure 13.1 [23]. When the grids are set at the same potential and consistent with their position in the spectrometer, ions pass unhindered from source to drift region; here the ion shutter is open. An imposed potential difference of ca 50–100 V between the two closely-spaced grids creates an electrostatic field far greater than the drift field that is typically around 220 V cm–1, so that ions are drawn to the grid wires and discharged: the ion shutter is now closed. Ions are formed commonly in the source region using a radioactive nickel foil, though other sources, including ultra violet (UV) discharge lamps and corona discharge, have been described. Ions are gated into the drift region in

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S

M 63Ni

I

D

G1 G2

F A

T

P

B

H

FIGURE 13.1  Schematic diagram of an ion mobility spectrometer: A, amplifier; B, metal shell; D, drift gas inlets; F, Faraday plate; G1, G2, grids constituting the ion shutter; H, heating tape; I, insulation rings; M, metal field rings; P coils for pre-heating sample and drift gases; S, sample gas inlet; and T, threaded support rod.

pulses of 30–300 μs-duration by opening and closing the ion shutter at frequencies of 20–100 Hz. The ions move under the influence of the uniform electrostatic field to the detector, a Faraday plate, where signal is generated. The amplified signal, displayed as a function of the time of arrival at the detector, that is drift time, constitutes the ion mobility spectrum. The separation of ions into individual swarms occurs according to their differences in mobilities as swarms drift from the ion shutter to the detector. The drift gas is usually either purified air or nitrogen and the flow (300–1000 cm3 min–1) of the drift gas is from the detector to the ion shutter, that is, counter to the ion drift direction. This gas flow is mixed with the sample-containing source gas (10–100 cm3 min–1) before exiting the instrument at the source end, so the entry of sample vapors into the drift region is suppressed in this configuration of gas flows. The time of drift (td) for an ion swarm in the drift region (of length, l) yields a drift velocity vd given by

vd =

l td

(13.1).

The drift velocity, when normalized for electric field strength, E, produces the mobility coefficient, K, as shown in Equation 13.2

vd = KE

(13.2).

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391

Because vd and hence K are temperature and pressure-dependent, values for K are usually normalized to 273 K and 760 mm Hg and are reported as the reduced mobility coefficient, Ko,

 273   P  Ko = K   T   760 

(13.3),

where T is temperature in kelvin and P is pressure in mm Hg. If the character of the ion does not change Ko has a constant value but, upon change of temperature, differences in ion hydration or clustering with other ambient molecules result in nonconstant Ko values. An ion under the influence of the electric field in the drift region acquires kinetic energy, some of which is lost by collision to the surrounding gas molecules. When an ion is to be accepted as thermal, it is important that the retained kinetic energy (1/2 mvd2 + 1/2 Mvd2 ) is not significant compared with thermal kinetic energy (3/2kbT ) as found in the average kinetic energy of an ion (KEav), which is approximated by the Wannier expression:

KEav =

3 1 1 kbT + mvd2 + Mvd2 2 2 2

(13.4),

where m is the mass of the ion, M is the mass of the drift gas molecule [24]. A calculation of these energies is illustrated for protonated 2,3-dimethyl pyridine with a drift velocity of 769 cm s–1 in a field of 280 V cm–1 at 350 K and 660 mm Hg of N2; the thermal energy term for the drift gas 3/2 kbT has the value 7.3 × 10 –21 J and the retained kinetic energy 1/2mvd2 + 1/2 Mvd2 has the negligible value of 6.8 × 10 –26 J. When this condition holds, a mobility spectrometer is said to be operating in the socalled low-field region and ions are regarded as thermalized. The low-field region is assumed usually when E/N is less than 2 Td, where E is the electric field (V cm–1), N is the number density of molecules (cm–3), and Td is the townsend (10 –17 V cm2). The low-field region is accessed readily with ion mobility spectrometers operating at atmospheric pressure but it is difficult to achieve satisfactorily with instruments that operate at pressures of ca 1 mm Hg. In the low-field region, the mobility coefficient at a fixed temperature is independent of field strength, which can be 100–600 V cm–1 [25]. The lower limit for E is determined practically by radial losses of ions to the walls of the drift tube; the upper limit is defined by electrical breakdown of gases in the supporting atmosphere inside the drift tube. An important property of an ion mobility spectrometer operating in the low-field region is that ion losses to the walls by radial diffusion do not introduce mass discrimination in the collected ion signal because the ratio of the radial spreading distance to the drift distance is independent of ion mass [24].

13.2.1 The Profiles of Ion Mobility Spectra Used to obtain Thermodynamic and Kinetic Data There are two approaches that may be taken to follow the course of an ion/molecule reaction occurring in an ion mobility spectrometer. The first is through the profile of the ion mobility spectrum alone, and the second is from mass spectral ion intensities.

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When possible, the first method is preferable because there is always the danger of mass discrimination, ion/neutral association, or collisional dissociation when ions pass from the high pressure of a mobility spectrometer to the vacuum of a mass spectrometer. Despite these complications, mass spectrometry has value for identifying ions because otherwise ion identity must be deduced intuitively by reference to known or anticipated reactions and ion behavior in a mobility drift tube. A single type of ion, that remains unaltered during the period following injection into the drift region to its arrival at the detector, produces a near-Gaussian peak in the ion mobility spectrum. The width of the peak is determined by a combination of the pulse width of the ion shutter and by Brownian motion [26]. A slight asymmetry in the peak arises from the increased axial diffusion time experienced by the late-arriving ions. When two ions formed in the source transit the drift region with no further change, two peaks are observed, as illustrated in Figure 13.2a for ions A+ and B + . Such spectra cannot provide quantitative physical chemical data because conditions in the ion source, such as concentration gradient of neutral molecules, electrostatic field, and reaction time, are not well defined. Early attempts to use this method to obtain proton affinity differences from the ratio of the intensities of protonated polycyclic aromatic hydrocarbons yielded only the order of proton affinities [27]. When a process occurring in the drift region relates the ions, the mobility spectrum may become either simpler or more complex than shown in Figure 13.2a. Nonetheless, when experimental conditions are controlled, the spectrum may be interpretable and, subsequently, may provide thermodynamic and/or kinetic information pertinent to the process or ion/molecule chemistry. Consider the simple (b)

8

Relative intensity

(c)

Relative intensity

A+ B+ 10

12

14

16

18

20

22

Drift time (ms) 1.2 Type 2 1 A+ 0.8 0.6 0.4 0.2 0 8

24

(d)

AB+

13

1.2 Type 1 1 0.8 0.6 0.4 0.2 0 8

18

A+and AB+

18

Type 3

Ion intensity

Ion intensity

(a)

A+ AB+ 8

10

12 14 16 18 Drift time (ms)

20

22

FIGURE 13.2  Schematic mobility spectra illustrative of ion/molecule processes: (a) Ions A+ and B+ are formed in the source and experience no reaction in the drift region; (b) equilibrium A +  + B = AB+ prevails throughout the drift region; (c) A +  + B → AB + in the drift region; and (d) AB + →A +  + B in the drift region.

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393

association reaction described by Equation 13.5, in which the ions have a single positive charge (this discussion applies equally to negatively-charged ions) A + + B = AB+



(13.5).

At atmospheric pressure, third-body stabilization of AB + is highly efficient and the reaction may be treated as second-order in the forward direction and first-order in the reverse direction. In addition, the concentration of B is usually much greater than the concentration of A+ , so that the reaction is pseudo-first order in the forward direction with a constant concentration of B. As detailed below, ion/molecule reactions or interactions may be investigated using several experimental designs, each of which has been demonstrated with specific features or advantages. The ion mobility spectra produced in these experimental configurations differ and will be designated Types 1, 2, and 3. 13.2.1.1 Type 1. Equilibrium A +  + B = AB + Exists Throughout the Source and Drift Region In the Type 1 experiment, both A + and AB + are formed in the source region and the concentration of B is uniform throughout both source and drift regions. When the concentration of B is much greater than that of the ions, the reaction will attain equilibrium prior to the ions reaching the shutter and equilibrium will prevail in the drift region. The charge spends part of the time on A and part of the time on AB so there is only one peak in the mobility spectrum (Figure 13.2b) and its arrival time (time of maximum ion intensity) depends on the relative equilibrium concentrations of A+ and AB + . The arrival time for this composite peak is intermediate between the arrival times of A+ and AB + without interactions (Figure 13.2a) and is the weighted ion number average of the ion mobilities, which is expressed by Equation 13.6 in terms of the ion mole fractions Xi and their individual arrival times ti

td = X A+ t A+ + X AB+ t AB+

(13.6).

13.2.1.2 Type 2. A + + B → AB + in the Drift Region In this category, A + ions and some AB + ions are formed in the source region, B is present at uniform concentration in the drift region, and the reaction has not gone to completion (that is, attained equilibrium) when ions are introduced into the drift region. Discrete peaks at t A+ and t AB+ are present for A + and AB + that pass unchanged through the drift region. Some AB + ions are formed as A + travels to the detector, the rate of the association reaction being given by:

−

d[A + ] = k[ A + ][ B] dt

(13.7),

where k is the rate constant. The rate of reaction is greatest near the shutter where the concentration of A + is highest, and AB+ ions formed here will arrive at the detector at a time close to t AB+ .

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Practical Aspects of Trapped Ion Mass Spectrometry, Volume V

The rate of reaction is least near the detector, where the concentration of A+ is the smallest, and ions AB + formed here will have spent most of their transit time as A + and will arrive at times close to t A+ . The ‘fill in’ intensity between the normal peaks for A + and AB + is lowest at t A+ and rises exponentially to t AB+ , as illustrated by Figure 13.2c. The same type of mobility spectrum, as is shown in Figure 13.2c for the association reaction, Equation 13.5, is observed when the reaction is a charge exchange, as in Equation 13.8, where B is again present at uniform concentration throughout the drift region A + + B → A + B+



(13.8).

13.2.1.3 Type 3. A + and AB + are Formed in the Source Region and Neither A Nor B is Present in the Drift Region The dissociation of AB + , formed in the source region and injected into the drift region, will be observable at a temperature consistent with the activation energy for dissociation; the higher the activation energy, the higher is the required temperature. Significant reaction in this first-order process can be observed when the rate constant is of the order of the reciprocal of the drift time, which is usually of ca 100 s–1; however, the drift time can be varied to a limited extent by changing the electrostatic field. The mobility spectrum will show two distinct peaks, at time t A+ for A + and at time t AB+ , the drift time for AB + without decomposition within the drift region. Ions arriving at the detector at intermediate times have spent the first part of their drift time as AB + and the second part as A + . The rate of reaction, given by Equation 13.9, is greatest at the entrance to the drift region, where the concentration of AB + is highest, and least at the detector. The plot in Figure 13.2d illustrates the resulting exponential ‘fill in’ of the spectra between the two discrete peaks with maximum intensity at t A+ . −



d [ AB+ ] = k[ AB+ ] dt

(13.9),

where k is the rate constant.

13.2.2 Examples Where Thermodynamic and Kinetic Data have been obtained from Ion Mobility Spectra Though IMS and ion mobility spectrometry/mass spectrometry (IMS/MS) methods may not be recognized widely for determining values for enthalpy, entropy, and kinetic constants, significant experience in the study of reactions at ambient or elevated pressures exists. In the discussion below, examples are drawn from gas-phase reactions for associations and displacements of ions using either combined mobilitymass spectrometry or, in some instances when the chemistry was well known, a drift tube alone. The order of presentation follows that used in the prior section. In a later discussion, reactions with electrons are described.

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13.2.2.1 Type 1. Ions in Equilibrium Showing a Single Peak in the Mobility Spectrum In dried air or nitrogen with ionization using a 63Ni source, the initial ionization event produces N + , N2+ , O + , and O2+ which lead, through a series of rapid ion/molecule reactions with the ubiquitous trace amounts of water, to the hydronium ion (H2O)nH + [20]. The subscript n denotes a range of values that depends on both the water concentration and the temperature. The equilibrium of the hydronium ion is shown in Equation 13.10,

(H 2O)n H + + H 2O = (H 2O)n+1H +

(13.10).

For example, using data from reference [28] and assuming equilibrium conditions with 1.0 ppmv (parts per million by volume) water at 300 K, the populations for n = 2, 3, 4, and 5 are 0, 21, 76, and 3%, respectively. At 400 K, the respective populations are 47, 53, 0.1, and 0%. Proton transfer from one or more of these hydrates to a molecule, present at a concentration much lower than that of water, which is present usually at a concentration of 1–10 ppmv, is often the initial step in forming an ion of interest. Though different experimental methods have been employed in the study of physical chemistry of the proton hydrate, it is not surprising that investigations have been made also with IMS given the importance of the hydronium ion as a reactant in IMS. An early attempt was made by Kim et al. to link the reduced mobility of the hydrated proton to the known range of n for (H2O)nH + in moist atmospheric air [29]. An ion mobility spectrometer interfaced to a mass spectrometer was used with a constant concentration of water throughout the drift tube of the mobility spectrometer, thereby ensuring a constant ratio of the equilibrium concentrations of the various hydrates in the drift region. In the absence of sample molecules, the hydrates constitute the major peak in the mobility spectrum, the reactant ion peak (RIP), whose drift time varies as the value of n changes with change of temperature. An ion/molecule association reaction is always exothermic, so that raising the temperature favors smaller clusters and vice versa. A larger cluster ion has lower mobility than does a smaller one, and so the drift time of the RIP decreases with increase of temperature while a lower temperature leads to a longer drift time. Each hydrate ion has a unique mobility and the drift time of the single peak in the spectrum should give a measure of the equilibrium distribution. The mobility, and hence the reduced mobility, increased as the temperature was raised, consistent with a reduction in the average value of n as the distribution shifted to the lighter, more mobile hydrates. The water concentration was not measured but was calculated by Equation 13.11 from the mass spectral intensities In and In–1 (presumably at one temperature, although this is not stated) together with the equilibrium constants Kn–1,n from the thermodynamic data of Kebarle et al. [30].

PH2O =

In I n−1K n−1,n

(13.11).

The distribution diagram for the proton hydrates was calculated over the whole temperature range with this water concentration and the equilibrium constants. The

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Practical Aspects of Trapped Ion Mass Spectrometry, Volume V

measured ion mobility over the whole temperature range is in good agreement with that obtained from the formula in Equation 13.12, which relates the mobility coefficient K to the ion/molecule interaction potential Ω, the measure of closest approach of ion and molecule rm, and their reduced mass μ [1],

K=

3  2π  16 N  µ kbT 

1/2

1 π rm2Ω

(13.12).

The same studies were reported for the hydrates of NO + and NH4 + , which are minor ions in the same system. When equilibrium exists in an ion/molecule reaction then the relative peak heights of the different hydrate ions, sampled from a mobility spectrometer through a small orifice into a mass spectrometer, give a direct measure of their equilibrium concentrations, provided there is no mass discrimination in the sampling process. Gheno and Fitaire applied this method to obtain thermodynamic data for the proton hydrate equilibria over the temperature range 300–473 K with N2 drift gas containing 3 ppmv water [31]. Van’t Hoff plots yielded the standard enthalpy and entropy values of Table 13.1 that show excellent agreement with National Institute of Standards and Technology (NIST) values [28] of both the enthalpy (–ΔrHo) and entropy (–ΔrSo) changes for the formation of (H2O)3H + but less so for (H2O)4H + . The reduced agreement with NIST values for (H2O)4H + is due probably to dissociation in the interface to the mass spectrometer of the higher, more fragile n = 4 hydrate. The enthalpy change for the association of N2 with NO + and to a lesser extent the entropy change are in good agreement with the values obtained by PHPMS at ca 4 mm Hg [32]. The data for such weakly-bound clusters as N2·NO + must always be treated with some skepticism because there is usually a danger that the ions detected are clustered with drift gas molecules during adiabatic cooling in the free-jet expansion between the mobility drift tube and the mass spectrometer [33]. However, it would be surprising if exactly the same relative ion intensities in the mass spectrum occurred in expansion from atmosphere pressure and also from 4 mm Hg, and the equality of the thermodynamic data for the formation of the N2 · NO + complex validates the results, the IMS data, and the method. Preston and Rajadhyax who employed a hand-held ion mobility spectrometer, similar to those used in military applications, studied the correlation between the reduced mobility for ion processes at equilibrium and the arrival time of the single peak in the mobility spectrum [34]. Equilibrium constants were determined as a function of temperature for the formation of proton-bound dimers MZH + as shown in Equation 13.13, where each of M and Z can be pyridine, 3-(3-methoxypropoxy) propanol (DPM), acetone, or water,

MH + + Z = MZH +

(13.13).

At equilibrium, the arrival or drift time td of the single peak is the number-weighted average of the drift times of the two constituent ions as described by Equation 13.6. When the times spent as the individual ions are t MH+ and t MZH+ , respectively, it follows that

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The Study of Ion/Molecule Reactions at Ambient Pressure

TABLE 13.1 Thermodynamic Data for Hydration Reactions from IMS/MS Determinations Reaction (H2O)2H +  + H2O = (H2O)3H +  (H2O)3H +  + H2O = (H2O)4H +  NO +  + N2 = N2 · NO + 

–ΔrHo (kJ mol−1)

–ΔrSo (J K−1 mol−1)

86 ± 4 (84 ± 5)a 58 ± 5 (73 ± 4)a 20 ± 4 (19 ± 1)b

109 ± 17  (94 ± 20)a 78 ± 17 (118 ± 8)a 58 ± 13 (71)b

Source: Gheno, F.; Fitaire, M. J. Chem. Phys. 1987, 87, 953–958. a Evaluated data in reference NIST. NIST Chemistry Webbook. 1998. b PHPMS data from reference Hiraoka, K.; Yamabe, S. J. Chem. Phys. 1989, 90, 3268–3273.



X MH+ a = t MH+ /td

and

X MZH+ = t MZH+ /td

(13.14),

and the measured reduced mobility for a peak at any temperature is related to the individual reduced mobilities by

K o = X MH+ K o MH+ + X MZH+ K o MZH+

(13.15).

When Equations 13.14 and 13.15 are combined, the equilibrium constant is given by Equation 13.16 in which Po is the standard pressure, 101 kPa, and PZ is the partial pressure of Z

K=

X MZH+ Po K MH+ − K o Po ⋅ = o ⋅ X MH+ PZ K o − K o MZH+ PZ

(13.16).

As the concentration of the neutral molecule Z was increased, the reduced mobility attained a limiting minimum value, calculated from the arrival time of the single peak. This value was taken to be K o MZH + , the concentration of MH + presumably being negligibly small. The term K o MH + was the reduced mobility in the absence of Z, and equilibrium constant measurements over a range of temperature yielded the results presented in Table 13.2. The standard enthalpy changes for acetone–water and pyridine–pyridine are in fair agreement with literature values but there is no agreement for pyridine–water. Some of the standard entropy changes are impossibly high and show little agreement with literature values. Although the method is sound, the instrument used for this study was not suited particularly to the determination of reliable thermodynamic data because the drift region was only 3.7 cm long. Giles and Grimsrud described an instrument designed specifically for the study of ion/molecule reactions [35]. The cylindrical drift tube was large, 40 cm long and 9 cm in diameter, and the moveable ion source allowed facile change in drift length.

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Practical Aspects of Trapped Ion Mass Spectrometry, Volume V

TABLE 13.2 Thermodynamic Data for the Reaction MH +  + Z = MZH + as Measured by Mobility Spectrometry M Acetone Pyridine Pyridine DPM

Z

–ΔrHo (kJ mol–1)

–ΔrSo (J K–1 mol–1)

Water Pyridine Water Acetone

99±10 (84) 139±25  (103) 44±9 (97) 67±7

226±50  (109) 260±80  (124) 50±50 (116) 45±6

Source: Preston, J.M.; Rajadhyax, L. Anal. Chem. 1988, 60, 31–34. Note: Values in brackets are PHPMS data from reference NIST. NIST Chemistry Webbook. 1998.

Ion mobility spectra were recorded using a Faraday plate with a small central orifice that permitted passage of ions for identification by a quadrupole mass spectrometer. Ion/molecule reaction rate constants and reaction enthalpies and entropies were determined using this IMS/MS instrument; one application followed the pioneering work of Preston and Rajadhyax [34] to measure the equilibrium constant for the association of CHCl3 and Clˉ. In this work, ions were formed in the source region and passed through a counter flow of CHCl3 in the drift region. The arrival time of the single peak, initially due to Clˉ, increased with increasing concentration of chloroform, suggesting the formation of Clˉ(CHCl3), as in Equation 13.17:

Cl − + CHCl 3 = Cl − (CHCl 3 )

(13.17).

The identity of this adduct ion was confirmed by the mass spectrum that contained both Clˉ and Clˉ(CHCl3). A limiting arrival time of the peak defined the concentration of CHCl3 at which essentially all the Clˉ was found in the adduct ion. When X Cl − and X Cl − ( CHCl3 ) are the equilibrium mole fractions of the two ions and tobs is the arrival time of the composite peak, which changes from to for Cl– to t1 for Clˉ(CHCl3), then:

X Cl − + X Cl − (CHCl3 ) = 1

(13.18)



X Cl − to + X Cl − ( CHCl3 ) t1 = tobs

(13.19)





X Cl − ( CHCl3 ) X Cl − K=

=

tobs − to [Cl − (CHCl 3 )] = [Cl − ] t1 − tobs

1 tobs − to ⋅ t1 − tobs [CHCl 3 ]

(13.20)

(13.21)

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399

so that

1 1 1 = + tobs − to K (t1 − to )[CHCl 3 ] t1 − to

(13.22).

A plot of (tobs–to) –1 vs [CHCl3]–1 yields a straight line with slope [K(t1–to)]–1. The mobility coefficient was determined at three different temperatures and ΔrHo = –75.7 kJ mol–1 and ΔrSo = –91.2 J K–1 mol–1 were obtained from the van’t Hoff plot; these values are in good agreement with listed values that range from –75.7 to –81.6 kJ mol–1 and –61.9 to –103 J K–1 mol–1, respectively [28]. An experiment with Brˉ forming Brˉ·CHCl3 found ΔrHo = –66.1 kJ mol–1 and ΔrSo = –88.2 J K–1 mol–1, the former value being appropriately smaller than for the Clˉ analog. The chloride anion is known as a useful reactant ion for IMS, particularly in the detection of explosives [1,2,36,37], as it forms complexes with molecules by ­bonding via hydrogen(s) rendered acidic by the presence of NO2 groups. Such complexes were not studied for explosives that in general have very low volatility, but rather for compounds of high volatility that are added in low concentration as chemical taggants. Information on the relative strength of binding between Clˉ and several potential taggants, 1,4-dinitrobenzene (DNB), 2,3-dimethyl-2,3-dinitrobutane (DMNB), and 2,3-dimethyl-2,4-dinitropentane (DMDNP) was obtained by Lawrence et al. from equilibrium measurements by IMS/MS [38]. The Clˉ reactant ion was formed in the source region by the incorporation of trace amounts of CH2Cl2 into the ultra high-purity nitrogen source gas; samples of each nitro compound (M) produced the Clˉ(M) adduct (Equation 13.23), which was sufficiently stable to traverse the drift region to the detector:

Cl − + M = Cl − (M)

(13.23).

A measure of the stability of each adduct was obtained by raising the temperature of the whole instrument to determine the highest temperature at which the adduct was observed in the mobility spectrum. The order of stability determined, Clˉ(DNB)  > Clˉ(DMDNP) > Clˉ(DMNB), is the same as the number of H atoms in a position α to the NO2 groups, that is, 4, 1, and 0. Further studies were made with DMNB because it has suitable properties, in particular vapor pressure, as a taggant. The standard enthalpy and entropy changes for the association of Clˉ with DMNB were determined by forming Clˉ in the source region and adding DMNB, in increasing and known concentrations, to the drift gas that flowed counter to the ions. A peak at time to when no DMNB was present was due to Clˉ. The single peak seen in the mobility spectrum with DMNB in the drift gas stream was identified as a mixture of Clˉ and Clˉ (DMNB) using an IMS/MS instrument. When the DMNB concentration was increased further, the peak shifted to a longer drift time as shown in Figure 13.3. As concentration was increased further, the drift time attained a constant and maximum value, t1; the sole component of the peak was mass-identified as Cl– (DMNB). Mass spectra for the composite peak at the lower concentrations of DMNB demonstrated the equilibrium of Equation 13.23. The interpretation of the results follows that of Giles and Grimsrud where a plot of (tobs –to) –1 vs [DMNB]–1 yielded a straight line with slope of [K(t1–to)]–1. The

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Practical Aspects of Trapped Ion Mass Spectrometry, Volume V

50 ppm DMNB

Signal intensity (arbitrary units)

9.3 ppm 2.7 ppm 0.7 ppm 0.2 ppm 0 ppm

5

10 15 Ion drift time (ms)

20

FIGURE 13.3  Ion mobility spectra as functions of the concentration of DMNB at 443 K. The peak at 0 ppm DMNB is the chloride ion alone and peaks with DMNB are due to the Clˉ(DMNB) adduct where drift time is dependent upon vapor concentration of DMNB in the drift tube. (Reproduced from Lawrence, A.H., et al., Int. J. Mass Spectrom. 2001, 209, 185–195. With permission from Elsevier.)

equilibrium constant K was determined at different temperatures and, from a van’t Hoff plot, ΔrHo = –92.1±3.1 kJ mol–1 and ΔrS o = –92.1±7.4 J K–1 mol–1 were obtained. 13.2.2.2 Type 2. Reaction Rate Constant Measurements Spectra of Type 2 were used for kinetic studies by Giles and Grimsrud who determined the rate constants for the SN2 displacement of Brˉ by Clˉ from methyl-, ethyl-, isopropyl-, and n-butyl-bromide at 398 K as per Equation 13.24 [35],

Cl − + RBr → RCl + Br −

(13.24).

The chloride ion was formed by dissociative electron capture by CCl4 in a 63Ni ionization source; n-alkyl bromide, at a known concentration, was present in the drift region. The traces in Figure 13.4 are ion mobility spectra obtained at three concentrations of methyl bromide. Figure 13.4a shows the Clˉ peak in addition to two small peaks, each marked with an asterisk, that arise from impurities; the small

401

The Study of Ion/Molecule Reactions at Ambient Pressure 0.08 0.07 0.06 0.05 0.04 0.03 0.02 0.01 0

(b)

0.06 0.04 0.03 0.02 0.01 0

(c)

(d)

Ion intensity (nA)

(a)

0.05 0.04 0.03 0.02 0.01 0 0.07 0.06 0.05 0.04 0.03 0.02 0.01 0 20

25

30

35

Drift time (ms)

FIGURE 13.4  Ion mobility spectra for the reaction of Clˉ with CH3Br at concentrations of (a) none, (b) 1.29 × 10l2, (c) 2.60 × 10I2, (d) 5.27 × 10l2 molecules cm–1. (Reproduced from Giles, K.; Grimsrud, E.P. J. Phys. Chem. 1992, 96, 6680–6687. With permission from the American Chemical Society.)

peaks were invariant with methyl bromide concentration and can be ignored. The intensity for Clˉ in the mobility spectra decreases as the Brˉ intensity increases with increasing concentration of CH3Br, as shown in Figure 13.4b through d. The contribution of each ion to the shape of the mobility spectrum was determined by concurrent mass spectrometry to obtain the relative mobility spectral area Ai assignable to each ion as a function of alkyl bromide (RBr) concentration. The pseudo-first order reaction rate constant for reaction 13.24, k’ = k24[RBr], is given by Equation 13.25 in which td is the arrival time, that is the reaction time, of Clˉ:

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Practical Aspects of Trapped Ion Mass Spectrometry, Volume V

k′ =



1  ACl − + ABr −  ln  td  ACl −

(13.25).

The graph of k’ vs [RBr] is a straight line of slope k24 and the value for k24 was duplicated in a different experiment involving mass spectrometric detection with the drift tube acting as a reactor with the shutter open continuously. The intensities of Clˉ and Brˉ were measured as a function of RBr concentration with reaction time the same as for the pulsed mode; a plot of ln( I Cl − /I Cl − + I Br − ) vs [RBr] yielded a straight line of slope –k24td. The results obtained for the four alkyl bromides by the area method and the mass spectrometric method are compared in Table 13.3 with those obtained from a PHPMS study completed at ca 4 mm Hg [39]. All the rate constants are much lower than the calculated average dipole orientation (ADO) collision rate constants, which are of the order of 2 × 10 –9 cm3 molecule –1 s –1, consistent with the inhibiting central barrier described by the double-well potential theory [40]. There is excellent agreement between the PHPMS and IMS results for ethyl bromide (EtBr) and i-PrBr, but there is a significant difference for methyl bromide (MeBr), which suggests that the difference is not an experimental artifact but might be due to the different pressure regimes. Less efficient stabilization of the initially formed Clˉ···CH3Br complex at the lower pressures could be the explanation. To confirm that the difference is real, Knighton et al. compared the IMS/MS rate constants at ambient pressure, 640 Torr, with PHPMS rate constants at 3 Torr over the temperature range 308–423 K [41]. A significantly-higher rate constant was found at the higher pressure, although it was still far below the collision rate. This result, interpreted in terms of the double-well potential theory, suggests that the higher pressure leads to increased stabilization of the short-lived entrance channel intermediate (MeBr)Clˉ*. From the IMS/MS results, the estimated depth of the central barrier below the incoming channel, 2.2 kcal mol–1, is identical with the value obtained from a high level calculation [42].

TABLE 13.3 Rate Constants (cm3 molecule –1 s –1) at 398 K by IMS for the Reaction Cl– + RBr→RCl + Br– Method RBr MeBr EtBr i-PrBr n-BuBr

Area

MS

3.4 × 10 1.1 × 10–11 8 × 10–13 2.2 × 10–11 –11

PHPMSa

3.4 × 10 1.3 × 10–11 7.6 × 10–13 2.2 × 10–11 –11

8.8 × 10–12 9.7 × 10–12 6.2 × 10–13 2.0 × 10–11

Source: Giles, K.; Grimsrud, E.P. J. Phys. Chem. 1992, 96, 6680–6687. a

Caldwell, G.; Magnera, T.F.; Kebarle, P. J. Am. Chem. Soc. 1984, 106, 959–966.

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The IMS/MS result cannot confirm that the high-pressure limit of kinetic behavior has been attained, but it demonstrates clearly that low-pressure experiments for such reactions cannot provide definitive information regarding the problem. There is no difference between the results for the reaction of Clˉ with EtBr and n-BuBr at 640 Torr and at 3 Torr, suggesting that the intermediates in these reactions have longer lifetimes than that of their methyl analog and that their high-pressure limit is attained even at 3 Torr. The upper pressure range of the mobility spectrometer was extended to enable a further study in the reaction of Clˉ with MeBr from 300 Torr to 1100 Torr N2 [43]. Over this range, the reaction rate constant increased by ca 25% demonstrating that the high-pressure limit was not attained even at 1100 Torr. The nascent collision complex must have a lifetime toward back dissociation that is much less than the ca 40 ps between stabilizing collisions. When the nitrogen drift gas was replaced by methane, the rate constant increased further. Better quenching of the intermediate (MeBr)Clˉ* by the more complex drift gas molecule is the most likely explanation for the increase. 13.2.2.3 Type 3. Dissociation of Adduct Ions Rate constants for the first-order dissociation of symmetrical proton-bound dimers, M2H + → MH +  + M, have been determined for organophosphorus compounds (M = 2,4-dimethylpyridine (DMP) and dimethyl methylphosphonate (DMMP)), where the shapes of the mobility spectra are of the form shown in Figure 13.2d [44]. Some proton-bound dimers decompose in the time taken for the ions to travel between the shutter and the detector plate, and this residence time was varied by changing the electrostatic drift field strength. Typical ion mobility spectra obtained at different field strengths are shown in Figure 13.5 and peaks were mass identified as: first peak, H + (DMP), the protonated monomer and second peak H + (DMP)2, the proton-bound dimer. The raised baseline between the peaks was due entirely to (DMP)H + , from the decomposition of the proton-bound dimer as in Equation 13.25

H + (DMP)2 → H + (DMP) + DMP

(13.25).

The reaction rate constant was determined in the following manner. The distance x from the shutter at which decomposition occurs at time tx is given by Equation 13.26, in which L is the shutter-detector plate distance, td is the drift time of (DMP)2H +, and tm is the drift time of (DMP)H +   t − tm  x = L  td − tm 



(13.26).

The value of tx is then given by

tx =

x xtd  t − tm  = = td   td − tm  vd L

(13.27).

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3.E+05

100 V cm–1

2.E+05 1.E+05 0.E+00

0

5

10

15

20

25

30

35

Drift time (ms)

Intensity (counts)

2.E+06

200 V cm–1

1.E+06

0.E+00

0

5

10

15

20

25

Drift time (ms)

Intensity (counts)

6.E+06

280 V cm–1

3.E+06

0.E+00

0

5

10

15

20

25

Drift time (ms)

FIGURE 13.5  Mobility spectra for DMP at three electric field strengths obtained in air at 350.4 K and 5 ppm moisture. (Reproduced from Ewing, R.G.; Eiceman, G.A.; Harden, C.S.; Stone, J.A., Int. J. Mass Spectrom. 2006, 255, 76–85. With permission from Elsevier.)

The concentration of ions from proton-bound dimer not decomposed at time tx is proportional to the area of the mobility spectrum from tx to the end of the ­proton-bound dimer peak. For the first-order decomposition of M2H + , a plot of the logarithm of this area vs tx is a straight line of slope –k, where k is the reaction rate constant. Examples of plots for the decomposition of (DMP)2H + from measurements obtained at 350 K and different field strengths are shown in Figure 13.6. The sudden drop in ion signal in each graph signifies the end of the proton-bound dimer peak. The figure demonstrates that the drift time of (DMP)2H + varies inversely with the field strength, and that the slope is independent of field strength. Values of k obtained at different temperatures enabled the determination of an activation energy Ea and

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In [(DMP) 2H* remaining]

17.5

280 260 240 220 200

17 16.5 16

180 160

15.5

140

15 14.5

120 100

14 13.5

0

5

10

tx (ms)

15

20

25

FIGURE 13.6  Plots of ion intensity for (DMP)2H + remaining at time ts at different field strengths E (V cm–1) at 349 K and 5 ppm moisture in the supporting atmosphere of the drift tube. (Reproduced from Ewing, R.G.; Eiceman, G.A.; Harden, C.S.; Stone, J.A., Int. J. Mass Spectrom. 2006, 255, 76–85. With permission from Elsevier.)

TABLE 13.4 Arrhenius Activation Energies and Pre-exponential Factors for the Reaction M2H + → MH +  + M in the Presence of Different Water Concentrations M DMP DMP DMMP DMMP DMMP

Water (ppmv)

T range (K)

Ea (kJ mol–1)

Log [A (s–1)]

5 2 × 103 5 5 × 102 5 × 103

338–58 311–42 478–98 478–98 478–98

94±2 31±5 127±3 130±2 115±1

15.9±0.4 6.3±0.7 15.6±0.3 15.3±0.4 14.5±0.3

Source: Ewing, R.G.; Eiceman, G.A.; Harden, C.S.; Stone, J.A. Int. J. Mass Spectrom. 2006, 255, 76–85. With permission.

pre-exponential factor A for the dissociation from an Arrhenius plot of ln k vs 1/T. Because some water vapor is always present in mobility drift gases, the experiments presented a favorable opportunity to examine any effects that water vapor may have on reaction rates. The results obtained with different water vapor concentrations are shown in Table 13.4. Of note is the relatively narrow temperature range over which measurements could be made due to the high activation energies for reaction, coupled with the small dynamic range of the mobility spectrometer. The narrow temperature range does not, however, preclude obtaining results with good precision. The pre-­exponential factor of ca 1015 s–1 is the maximum expected for unimolecular decompositions [45].

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A measure of the accuracy of the results can be obtained with the knowledge that there should be little or no reverse activation energy for the decomposition, and the activation energy will differ by only RT from the enthalpy of dissociation. The value of Ea obtained for DMP at 5 ppmv water is in excellent agreement with the expected ca 92 kJ mol–1 for symmetrical N2–base dimers [28]. Similarly, the activation energies for DMMP are consistent with the expected ca 134 kJ mol–1 for symmetrical oxygen-base dimers. The activation energy and pre-exponential factor for the decomposition of (DMP)2H + at high water concentration are anomalously low and suggest the influence of a displacement reaction

H 2O + (DMP)2H + → (DMP)H + (H 2O) + DMP

(13.28),

in which the symmetric proton-bound dimer becomes an asymmetric protonbound dimer ((DMP)H + H2O), the activation energy being the difference in bonding enthalpy of DMP and water to (DMP)H + . Lower reduced mobility values for (DMP) H + at the higher water concentration of 2 × 103 ppmv implies, and mass spectra confirmed, that (DMP)H + was indeed hydrated in the experimental temperature range. Data from PHPMS [46] suggest a difference of ca 36 J K–1 mol–1, and the difference of 63 J K–1 mol–1 in Table 13.4 may imply that more than one water molecule is involved in the reaction. The much lower entropy change expected for a displacement reaction compared with unimolecular dissociation is also consistent with the lower pre-exponential factor. The dissociation of (DMMP)2H + occurred at a much higher temperature than that of (DMP)2H + , and the slight effect of water vapor on the kinetics shows that the reaction was mainly unimolecular even at 5 × 103 ppmv water.

13.2.3 The Kinetics of Thermal Electron Capture and Thermal Electron Detachment Ion sources operating at atmospheric pressure in N2 or air provide an abundant source of thermalized electrons. In the absence of molecules with suitable electron affinity, and with an ion mobility spectrometer operating in the negative ion mode, electrons are injected into the drift region to arrive at the detector about 100 times faster than any ion. Suitable molecules present in the drift region may capture electrons, leading to a decrease in electron signal and a negative ion signal at much longer times. Anions formed in the source region by attachment of thermalized electrons, and injected into the drift region in the absence of attaching molecules, may thermally lose the electron at suitable temperatures and produce an interpretable mobility spectrum. Mobility spectrometers operating at atmospheric pressure have been employed to obtain reaction rate constants for both electron capture and for thermal electron detachment studies and these methods are discussed separately below. 13.2.3.1  Electron Capture Spangler and Lawless [47] measured the rate constant for dissociative electron capture by chlorobenzene by monitoring the production of Clˉ. Electrons traveling down the drift tube to the detector encountered chlorobenzene molecules from an exponential dilution

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flask whose concentration varied in a well-defined manner. The Clˉ ion signal was related to the chlorobenzene concentration and a rather complex mathematical modeling of the system gave a rate constant of 7.1 (±3.1) × 10 –11 cm3 s–1 at 473 K, in agreement with experimental data from the more conventional swarm beam technique [48]. Mayhew and co-workers constructed a mobility spectrometer–mass spectrometer combination that has been used extensively to determine the kinetics of the attachment of low energy electrons to halogen-containing molecules at atmospheric pressure [49–56]. Attachment rate coefficients have been determined in two ways. One method is by monitoring the attenuation of a pulse of electrons passing through the drift region containing a known concentration of attaching molecules, and the second by determining the axial distribution of the resulting anions. Excellent agreement between the results obtained by the two methods and with results from the literature was found for SF6 [56]. A pulse of electrons passing through the drift region is attenuated exponentially by radial scattering to give a detector signal Io. In the presence of a constant concentration of an attaching molecule M the signal is further attenuated to a value I, as in

I = I oe − αL [ M ]

(13.29),

where α is the density-normalized electron attachment coefficient and L is the drift length. A plot of ln(I/Io) vs the concentration of M has slope –αL. The rate constant for electron attachment k is obtained from αL with the substitution L = wt where t is the electron arrival time and w is the mean electron drift velocity. The value of w, which is a function of E/N, is different for each drift gas and is determined theoretically (values for nitrogen are available in the literature [37]). The electron attachment rate constant for SF6 in nitrogen at ambient temperature and pressure showed a smooth decline with increasing E/N over the range of 0.39– 0.78 Td [56]. As shown in Figure 13.7, the results obtained by IMS agree closely with those obtained by the well-established high-pressure swarm technique [57]. A further series of experiments with E/N from 0.05 to 0.9 Td confirmed this excellent agreement between the two methods [55]. Both the mobility and the swarm experiments showed that the electron energy distribution in nitrogen is not thermal, even at E/N  M Th are ejected resonantly with a broadband waveform. Figure 15.17 shows the scan function of this isolation method. In this method, ions with mass/charge ratio M Eject <M

Figure 15.17  The process of ion isolation is executed sequentially. First, lower masses are ejected with a modified mass-selective axial instability scan that is, essentially, the same as normal analytical scanning. Second, higher masses are ejected resonantly with a broadband waveform. The ejection order may be reversed to avoid product ions of higher m/z-values. WF1 is a notch waveform to eject unwanted ions during ionization and the post-ionization period; WF2 is a broadband waveform to eject higher mass ions during higher mass isolation period.

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refers to the number of digital-to-analog conversions effected, over a given range of RF voltage, to obtain a stepped RF voltage profile from a linear voltage profile. The relationship of qz × m to RFDAC can be expressed as a first-order approximation by Eq. (15.1)

q z × m = A + B × RFDAC

(15.1)

Usually, ions of m/z 69 and 414 from the calibration chemical PFTBA are used to find the values for the two parameters, A and B. The trapping frequency calibration is carried out near qz = 0.845 at a fixed RF trapping field. A linear relation between qz × m and RFDAC is true only under ideal conditions but, as a first-order approximation, it works well for this two-step isolation method in a non-ideal quadrupole ion trap. Typically, in an ion trap for which the oscillation frequency of the RF ­potential is 1 MHz, the frequency error of the calibration is less than 1 kHz, which ­corresponds to an error of  90% for stable precursor ions (as discussed above), as shown in Figure 15.18. Because the broadband waveform is applied for limited time only, the frequency spectrum of the broadband is not a perfect rectangular shape, as is shown in Figure 15.19. The tailing of the high-frequency side will excite modestly the precursor ions. Some of the chemically-unstable ions, that is, ions having low fragmentation threshold energy, may gain sufficient energy to be fragmented in the higher-mass isolation process. For these unstable ions, the isolation window should be ca 3–5 Th. The wider isolation window combined with reduced amplitude of the high-mass ejection waveform can minimize the loss of unstable precursor ions. 15.2.2.1.2  Notch Isolation Application of the ‘Notch’ waveform for ion isolation is another practical technique that is employed in GC/MS/MS. As discussed above, the precision of the trapping frequency calibration is ca 1 kHz. The difference between the secular frequencies of ion motion for ions M + and [M + 1] + increases rapidly as the qz -values of the ions approach 0.908, at which the qz -axis intersects the βz = 1 boundary of the stability diagram. Thus, as a practical compromise, the notch waveform isolation is performed typically at qz > 0.8. At a qz -value of ca 0.8, unit mass of isolation resolution is achievable, as can be seen in Figure 15.18. In the isolation process, the magnitude of the RF trapping field is set to a value such that the secular frequency of the chosen precursor ions falls within the width of the frequency window of the notch waveform, as is shown in Figure 15.20. The frequency bandwidth of the notch waveform covers the secular frequencies of all unwanted ion species, typically 5 kHz–500 kHz in a 1 MHz trapping field. Thus, all unwanted ions would be ejected resonantly with the notch waveform, leaving the chosen precursor ions confined within the ion trap.

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Base peak: 263.9, Base amount: 4093 Ion: 2000 us, Segement: 1, C

263.9 3136

3.0

k Counts

2.5 2.0 1.5 1.0 0.5 0.0 257.5

260.0

262.5

Scan number: 8, Time: 0.116 min. RIC: 12139, Ion range: 256.5-270.5 m/z

267.5

270.0

Base peak: 263.9, Base amount: 4035 Ion: 2000 us, Segement: 1, C

263.9 3102

3.0 2.5 k Counts

265.0

m/z

2.0 1.5 1.0 0.5 0.0 257.5

260.0

262.5

m/z

265.0

267.5

270.0

Figure 15.18  Top, a pseudo-product ion mass spectrum of m/z 264 of PFTBA but without collision-induced dissociation (CID); the mass spectrum was acquired with default isolation parameters and isolation window of 1 Th. Bottom, a full scan mass spectrum of PFTBA obtained with the same duration of ionization and showing both the m/z 264 peak and the 13Cisotopomer peak at m/z 265. By comparison, loss of the m/z 264 ion during the isolation process is essentially zero for this chemically-stable ion. For chemically-unstable ions, loss of precursor ion during mass-selective isolation can be minimized by using an isolation window of 3–5 Th.

Several methods for constructing a notch waveform have been proposed [34–36]. Marshall developed originally the SWIFT technique [34] for Fourier transform ion cyclotron resonance, FT-ICR, spectrometry.* However, because the trajectories of trapped ions in each of an ICR cell and a quadrupole ion trap are characterized by secular frequencies of ion motion, the SWIFT technique can be applied also to the quadrupole ion trap. The SWIFT technique is able to generate a near perfect notch * For a detailed discussion of FT-ICR see Volume 5, Chapter 5: Fourier Transform Ion Cyclotron Resonance Mass Spectrometry in the Analysis of Peptides and Proteins by Helen J. Cooper.

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0.4

0.2

0

0

100

200 300 Frequency (kHz)

400

500 Expanded

0.4 0.2 0 450

460

470

480

490

Figure 15.19  The frequency spectrum of the broadband waveform used to eject higher mass ions. The expanded view of the spectrum (bottom right corner) showed clearly that the spectrum tailed into higher frequency area.

window when a quadratic phase relation is applied to its frequency components and the first quarter and fourth quarter of the time domain signals are apodized, as shown in Figure 15.21a and b. A quadratic phase relationship results in the waveform power being distributed throughout most of the time period such that the required dynamic range of the electronics will decrease. By nature, the quadratic phase SWIFT waveform is a pseudofrequency sweep waveform. The length of the SWIFT waveform is fixed. When the waveform is terminated in the middle of the length, the frequency spectrum will be distorted, as shown in Figure 15.21c. Figure 15.22 shows the time and frequency domain signals with random frequency phases. Both the waveform power and the frequency components are distributed uniformly throughout the entire time period. However, the magnitude-values that cross the frequency domain in random phase are not as uniform as those in SWIFT, as shown in Figure 15.22b. The edges of the notch window with random phase are not as sharp as those with quadratic phase SWIFT. Louris and Taylor [35] proposed a notch waveform that is a compromise between a SWIFT waveform and a random phase notch waveform; it is relatively more uniform in frequency components throughout the entire time period than is the SWIFT waveform. However, its frequency spectrum is not as flat as that of SWIFT. Generally, there is a trade-off between the dynamic range of the time signal and the flatness and notch-window sharpness of the frequency spectrum. Depending on the manner in which noise and the filter are generated, the Filtered

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0.2

Move precursor ion to higher q

a

Position of precursor in stability diagram

0

–0.2 0.0

0.4 Precursor ion

Notch waveform

q

0.8

1.2

Frequency spectrum of notch waveform Amplitude Notch window

Fourier transform Frequency

Figure 15.20  The basic concept of notch waveform isolation. In the isolation process, the working point of precursor ions is moved first to a qz -value at which the secular frequency of precursor ions lies inside the window of the notch waveform. Subsequently, the notch waveform is turned on to eject all unwanted ions. Due to the limited duration of application of the notch waveform, the window is not a perfect box as is seen in the bottom picture of this figure.

Noise Field (FNF) notch waveform [36] will have a performance somewhere between that of the quadratic SWIFT notch waveform and the random phase notch waveform. Buttrill has shown that in a notch waveform, the amplitude of each frequency component should be weighted [37]. He suggested a formula, (Ai/An) = (Mn/Mi)x, in which 0.5 400... 724.0>... 802.0>500:8... 880.0>600... 960.0>700:970 [2...

100 4

KCounts

75 50

10

5–1 5–2 6–1

3

7

6–2

8

25

9

0 7

8

9

10 Minutes

11

12

13

Figure 15.44  PBDE MS/MS Chromatogram, 50 ppb concentration (100 ppb for BDE 209). See Table 15.2 for peak names.

Table 15.2 The Analysis of PBDE Congeners in Accordance with the RoHS Regulation. The Peak Number in the Table Refers to the Peaks Labeled in Figure 15.44 Peak Number 3 4 5–1 5–2 6–1 6–2 7 8 9 10

PBDE Isomer BDE 28 BDE 47 BDE 99 BDE 100 BDE 153 BDE 154 BDE 183 BDE 205 BDE 206 BDE 209

15.3.3.4 Ion Trap Analysis with Liquid Chemical Ionization (CI) Reagents: USEPA Method 521 Ion traps can be configured readily to use liquid reagents for CI directly inside the ion trap cavity. Low vapor pressure liquids, such as acetonitrile (CH3CN) or methanol (CH3OH), can be used as CI reagents. The sequence of reactions is as follows:

CH3CN + e – → CH3CN+• + 2e –

(15.2)

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(a)

(b)

RoHS Matrix 4, taken between 10 other matrix injections RSD 10.8% Raw Area

Peak Area

150000 100000

Series1

50000 0

1

2

3

4 5 6 7 Injection Number

8

9

10

Figure 15.45  Decabromodiphenyl ether, congener BDE-209: (a) upper, total ion chromatograph showing detection of BDE-209 in an acrylonitrile butadiene styrene (ABS) plastic extract; (a) lower, product ion mass spectrum of BDE-209 showing the loss of Br2 from each of the ions of the molecular ion cluster; (b) %RSD in the chart is obtained from raw peak area data for a standard solution run after 10 injections of the ABS extract.



CH3CN+• + CH3CN → CH3CNH+ + CH2CN•

(15.3)



CH3OH + e – → CH3OH2+• + 2e –

(15.4)



CH3OH +• + CH3OH → CH3OH2+ + CH3O•

(15.5)

where the protonated molecules CH3CNH + and CH3OH2+ are CI reagent ions. The basic steps are: (a) form and trap reagent ions in the ion trap; (b) remove unwanted ions formed by EI using applied waveforms, leaving only CI reagent ions

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Technology Progress and Application in GC/MS and GC/MS/MS

Table 15.3 The Accuracy and Precision of the Seven Nitrosamines Listed in EPA Method 521 Using the CI/MS/MS Technique Compound Name NDMA NMEA NDEA NDPA NPYR NPIP NDBA

Meas.Conc. (ppb)

Accuracy (%)

0.934 0.986 0.997 1.056 0.904 0.924 0.896

93.4 98.6 99.7 105.6 90.4 92.4 89.6

Precision (RSD%) 7.30 11.49 3.08 10.09 5.08 4.55 5.42

Note: These data are based upon 11 injections of a standard solution of each Nitrosamine at a concentration of 1 ppb.

in the ion trap; (c) reagent ions react with sample to form protonated molecules or adduct ions; and (d) ions ejected in sequential mass order to form the mass spectrum. The technique is applicable particularly to compounds that yield multiple fragments (thus low response) under normal EI conditions. It is also useful for identifying and/ or confirming the molecular weight of a compound. USEPA Method 521 is used to determine the concentration of certain nitrosamines in source water and finished drinking water. Early health effects or toxicity data suggest that nitrosamines, in general, are powerful carcinogens [62]. Therefore, there is a need for an analytical method for the detection of nitrosamines at very low concentrations (parts-per-trillion levels or ppt) in finished drinking waters and source waters. Nitrosamines under normal EI conditions have very poor response, with multiple fragment ions being formed of low mass/charge ratio. CI provides protonated ions with much better response, and MS/MS adds specificity to the analysis. Nitrosamines provide a good example of how a specific ion trap technique can solve a tough analytical problem. These compounds are extracted from the water sample using a form of activated carbon, so matrix interference can become significant in waters that contain a high total organic carbon (TOC) content. The data shown in Table 15.3 illustrate the excellent accuracy and precision of the CI/MS/MS technique for the seven nitrosamines at a concentration of 1 ppb. These data are based upon 11 injections of a standard solution. A TIC of typical target compounds, to which the CI/MS/MS technique is applied, is shown in Figure 15.46. 15.3.3.5 Analysis of Polychlorinated Biphenyls (PCBs) by Ion Trap Mass Spectrometry Polychlorinated biphenyls (PCBs) exist as 209 individual congeners, exhibiting all the variations of position and number of chlorine substitutions in a biphenyl molecule.

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Practical Aspects of Trapped Ion Mass Spectrometry, Volume V

250

NPYR

NMEA

TIC NDBA

NDEA

200

NPIP

NMOR

kCounts

150 100 50

NDMA NDMA-d6(Surr.)

0 15

NDPA NDPA-d14((IS)

20

Minutes

25

30

Figure 15.46  CI/MS/MS TIC of some common nitrosamines listed in USEPA 521. Extract concentration is 50 ppb for each nitrosamine.

Each PCB congener is named according to the positions of chlorine substitution on the two phenyl rings of biphenyl, and the toxicity of PCBs correlates strongly with their structures. The toxicity of PCB mixtures is due principally to a small group of non-ortho and mono-ortho-substituted congeners [63]. USEPA Method 505 [64] is used for the determination of PCBs and other pesticides in both ground and surface water. A sample is prepared by extracting a small volume, typically 40 mL, with 2 mL of hexane. The hexane layer is removed and analyzed by gas chromatography. The method uses electron capture detection (ECD) for added sensitivity for halogenated compounds. Although ECD is a very sensitive detector for this analysis, it is prone to matrix interference and can result in false positive identification due to co-eluting peaks. Mass spectrometry can overcome this problem, however the sensitivity of the technique in full mass scan or SIM can be challenging in relation to the micro-extraction sample preparation procedure described in EPA Method 505. Current ion trap mass spectrometers, using a full mass scan for many compounds, can obtain very similar sensitivity to that achievable with ECD. Figure 15.47  illustrates the detection and identification, by ion trap mass ­spectrometry, of PCB isomer 2,3-dichlorobiphenyl at a concentration of 0.05 ppb (1.75 pg injected on-column). The PCBs were extracted using the micro-extraction technique listed in USEPA Method 505. Tables 15.4 and 15.5 illustrate that the compounds can be detected at levels similar to those attainable with ECD with excellent precision and accuracy. A set of replicates, spiked at low concentrations in the aqueous sample (0.025 to 0.25 ppb) of polychlorinated biphenyl (PCB) congeners in reagent and surface

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Figure 15.47  2,3-Dichlorobiphenyl at a concentration of 0.05 ppb in the aqueous sample (0.75 pg injected on-column). The upper half of the figure is an extracted ion mass chromatogram for m/z 152 + m/z 222. The lower half of the figure is a full scan mass spectrum of the same peak.

Table 15.4 Calibration Ranges Studied by Ion Trap Mass Spectrometry PCBs mono, di and tri tetra, penta and hexa hepta and octa deca

Aqueous Concentration (ppb)

Conc. on Column (pg)

0.025–5 0.05–10 0.075–15 0.125–25

0.875–175 1.75–350 2.625–525 4.375–875

Note: The aqueous concentration refers to the final concentration of the listed PCB isomers spiked into laboratory reagent water and extracted using the procedure described in EPA method 505. The second column lists the actual amount of the PCB isomers that were injected into the analytical system from the resulting aqueous extractions.

waters, was extracted and run in EI full mass scan mode for the determination of Method Detection Limits (MDL). The MDL in USEPA Method 505 is calculated based on the standard deviation of quantitative results multiplied by Student’s t at 99% confidence level [65].

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Practical Aspects of Trapped Ion Mass Spectrometry, Volume V

Table 15.5 Method Detection Limits (MDLs) of PCBs by Full Scan Ion Trap Mass Spectrometry in Reagent Water and Surface Water PCBs

Reagent Water (n = 8)

Surface Water (n = 16)

mono di tri tetra penta hexa hepta octa deca

0.010 0.011 0.010 0.009 0.017 0.016 0.014 0.017 0.082

0.010 0.015 0.014 0.024 0.053 0.040 0.068 0.085 0.221

Note: The units are μg L–1. A total of eight spiked samples for reagent water and 16 spiked samples for surface water were used in the statistical calculations based upon the MDL procedure outlined in EPA Method 505.

15.4 SUMMARY Since the middle 1990s, numerous efforts on fully-AMDs have made GC/MS and GC/MS/MS ion trap mass spectrometers to be practical and mature commercial products. Since then, GC/MS and GC/MS/MS ion traps have grown from novel research instruments into routine, widely-applied analytical instruments. GC/MS and GC/MS/MS ion trap instruments have reached a high level of maturity as they have grown in the directions of higher performance, such as faster scan speed, higher mass resolution, and extended charge capacity. The advent of the high-­performance linear ion trap has provided the opportunity for GC/MS and GC/MS/MS to grow even further in the future. The GC/MS applications discussed above demonstrate clearly that ion traps provide excellent data for applications, despite a history of poor performance in early ion trap designs. Qualitative and quantitative analysis in heavy matrices are possible because increased ion trapping capacity and ion population control is available in modern instrumentation. The technology has been accepted for use with major USEPA methods as a routine analytical tool for challenging environmental samples. The analyzer is versatile, because scan modes such as MS/MS, liquid CI, hybrid CI, and full scan mass spectrometry can be performed on the same instrument. This instrumental versatility reduces cost and increases specificity by providing more information about the molecules under study.

ACKNOWLEDGMENTS The authors would like to thank Dr. Barbara Bolton, Dr. Kenneth Newton, and Dr. Haibo Wang for their helpful discussions and useful data.

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References











1. Paul, W.; Steinwedel, H. Apparatus for Separating Charged Particles of Different Specific Charges, US Patent 1960, 2,939,952. 2. March, R.E.; Todd, J.F.J. Quadrupole Ion Trap Mass Spectrometry, Second edition of Quadrupole Storage Mass Spectrometry. Chemical Analysis Series, vol. 165. John Wiley, Hoboken, New Jersey, 2005. 3. Stafford, G.C., Jr.; Kelley, P.E.; Stephens, D.R. Method of Mass Analyzing a Sample by Use of a Quadrupole Ion Trap, US Patent 1985, 4,540,884. 4. Stafford, G.C., Jr.; Kelley, P.E.; Syka, J.E.P.; Reynolds, W.E.; Todd, J.F.J. Recent improvements in and analytical applications of advanced ion trap technology. Int. J. Mass Spectrom. Ion Processes. 1984, 60, 85–98. 5. Kelley, P.E.; Stafford, G.C. Jr.; Syka, J.E.P.; Reynolds, W.E.; Louris, J.N., Amy, J.W.; Todd, J.F.J. New advances in the operation of the ion trap mass spectrometer. Proc. 33rd ASMS Conference on Mass Spectrometry and Allied Topics, San Diego, CA, 1985, 707–708. 6. Syka, J.E.P.; Louris, J.N.; Kelley, P.E.; Stafford, G.C. Jr.; Reynolds, W.E. Method of Operating Ion Trap Detector in MS/MS Mode, US Patent 1988, 4,736,101. 7. Louris, J.N.; Schwartz, J.C.; Stafford, G.C. Jr.; Syka, J.E.P.; Taylor, D.M. The Paul ion trap mass selective instability scan: trap geometry and resolution. Proc. 40th ASMS Conference on Mass Spectrometry and Allied Topics, Washington DC, 1992, 1003–1004. 8. Franzen, J. Simulation study of an ion cage with superimposed multiple fields. Int. J. Mass Spectrom. Ion Processes. 1991, 106, 63–78. 9. Splendore, M.; Marquette, E.; Oppenheimer, J.; Huston, C.; Wells, G.J. A new ion ejection method employing an asymmetric trapping field to improve the mass scanning performance of an electrodynamic ion trap. Int. J. Mass Spectrom. 1999, 190/191, 129–143. 10. Wells, G.J.; Wang, M.; Marquette, E.G. Mass Scanning Method Using an Ion Trap Mass Spectrometer, US Patent 1998, 5,714,755. 11. Schwartz, J.C.; Senko, M.W.; Syka, J.E.P. A two-dimensional quadrupole ion trap mass spectrometer. J. Am. Soc. Mass Spectrom. 2002, 13, 659–669. 12. Stafford, G.C. Jr.; Taylor, D.M. Method of Increasing the Dynamic Range and Sensitivity of a Quadrupole Ion Trap Mass Spectrometer, US Patent 1992, 5,107,109. 13. Schwartz, J.C. Do space charge effects limit LC quadrupole ion trap performance. Proc. 9th Sanibel Conference on Mass Spectrometry, Sanibel Island, FL, 1997. 14. Brekenfeld, A.; Kaplan, D.A.; Hartmer, R.; Wilson, J.; Gebhardt, C.; Schubert, M. The right place and the right time: increasing the capacity in modern 3-D ion traps. Proc. 55th ASMS Conference on Mass Spectrometry and Allied Topics, Indianapolis, IN, 2007. 15. Mordehai, A.; Miller, B.; Bai, J.; Brekenfeld, A.; Baessmann, C.; Schubert, M.; Hosea, K. Improved 3D ion trap-ion detector coupling and techniques for evaluating exact ion trap capacity. Proc. 52nd ASMS Conference on Mass Spectrometry and Allied Topics, Nashville, TN, 2004. 16. George, J.E.; III, Specht, A.; Newton, K.; Wells, G. A comparison of the spectral charge capacity between two ejection methods. Proc. 54th ASMS Conference on Mass Spectrometry and Allied Topics, Seattle, WA, 2006. 17. Libong, D.; Bruneau, S.P.C.; Rogalewicz, F.; Ricordel, I.; Bouchonnet, S.J. Adsorptiondesorption effects in ion trap mass spectrometry using in situ ionization. Chromatog. 2003, 1010 (issue 1), 123–128. 18. Taylor, D.M.; Amy, J.W.; Stafford, G.C. Jr. Metal Surfaces for Sample Analyzing and Ionizing Apparatus, US Patent 1991, 5,055,678.

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19. Brittain, R.; Wang, M. Surface Coating to Improve Performance of Ion Trap Mass Spectrometers, US Patent 1997, 5,633,497. 20. McLuckey, S.A.; Glish, G.L.; Asano, K.G.; Van Berkel, G.L. Self chemical ionization in an ion trap mass spectrometer. Anal. Chem. 1988, 60, 2312–2314. 21. Booth, M.M.; Stephenson, J.L.J.; Yost, R.A. Gas chromatography/ion trap mass spectrometry using an external ion source. Proc. 41st ASMS Conference on Mass Spectrometry and Allied Topics, San Francisco, CA, 1993, 716a–716b. 22. Bier, M.E.; Syka, J.E.P.; Taylor, D.M.; Fies, W.J. Ion Source Assembly for an Ion Trap Mass Spectrometer and Method, US patent 1998, 5,756,996. 23. Wells, G J.; Yee, P.P.; Ruport, M.A.; Huston, C.K. Pulsed Ion Source for Ion Trap Mass Spectrometer, US Patent 2001, 6,294,780. 24. Louris, J.N.; Syka, J.E.P.; Kelley, P.E. Method of Operating Quadrupole Ion Trap Chemical Ionization Mass Spectrometry, US Patent 1987, 4,686,367. 25. Strife, R.J.; Keller, P.J. Ion trap ionization mass spectrometry-RF/DC for isolating unique reactant ions. Org. Mass Spectrom. 1989, 24(3), 201–204. 26. March, R.E.; Todd, J.F.J. eds. Practical Aspects of Ion Trap Mass Spectrometry. Vol. 3, “Chemical, Environmental, and Biomedical Application”, Ch. 7, “Chemical Ionization in Ion Trap Mass Spectrometry”, p. 239–253, by Creaser, C.S. Modern Mass Spectrometry series, CRC Press, Roca Baton, FL, 1995. 27. Berberich, D.W.; Heil, M.V.; Johnson, J.V.; Yost, R.A. Mass-selection of reactant ions for chemical ionization in quadrupole ion traps and triple quadrupole mass spectrometers. Int. J. Mass Spectrom. Ion Processes. 1989, 94, 115–147. 28. Van Pelt, C.K.; Carpenter, B.K.; Brenna, J.T. Studies of structure and mechanism in acetonitrile chemical ionization tandem mass spectrometry of polyunsaturated fatty acid methyl esters. J. Am. Soc. Mass Spectrom. 1999, 10, 1253–1262. 29. Brandt, S.D.; Freeman, S.; Fleet, I.A.; Alder, J.F. Analytical chemistry of synthetic routes to psychoactive tryptamines Part III. Characterisation of the Speeter and Anthony route to N,N-dialkylated tryptamines using CI-IT-MS-MS. Analyst 2005, 130, 1258–1262. 30. Hunt, D.F.; Stafford, G.C.; Crow, F.W.; Russell, J.W. Pulsed positive negative ion chemical ionization mass spectrometry. Anal. Chem. 1976, 48, 2098–2104. 31. March, R.E.; Todd, J.F.J. eds. Practical Aspects of Ion Trap Mass Spectrometry. Vol. 3, Ch. 2, “Ion Trap as Tandem Mass Spectrometers”, pp. 27–88, by March, R.E.; Strife, R.J.; Creaser, C.S. Modern Mass Spectrometry series, CRC Press, Roca Baton, FL, 1995. 32. March, R.E.; Todd, J.F.J. eds. Practical Aspects of Ion Trap Mass Spectrometry. Vol. 3, Ch. 4, “Practical Ion Trap Technology: GC/MS and GC/MS/MS”, pp. 121–185, by Yates, N.A.; Booth, M.N.; Stephenson, J.L., Jr.; Yost, R.A. Modern Mass Spectrometry series, CRC Press, Roca Baton, FL, 1995. 33. Wells, G.J. Quadrupole Trap Improved Technique for Ion Isolation, US Patent 1993, 5,198,665. 34. Marshall, A.G.; Ricca, T.L.; Wang, T.L. Tailored Excitation for Trapped Ion Mass Spectrometry, US Patent 1988, 4,761,545. 35. Louris, J.N.; Taylor, D.M. Method and Apparatus for Ejecting Unwanted Ions in an Ion Trap Mass Spectrometer, US Patent 1994, 5,324,939. 36. Kelley, P.E. Mass Spectrometry Method Using Notch Filter, US Patent 1992, 5,134,286. 37. Buttrill, S.E. Jr. Quadrupole Ion Trap Method Having Improved Sensitivity, US Patent 1994, 5,300,772. 38. Wang, M.; Lee, D.; Newton, K.; Schachterle, S. High-Resolution Ion Isolation Utilizing Broadband Waveform Signals, US Patent 2008, 7,378,648. 39. Schwartz, J.C.; Syka, J.E.P.; Quarmby, S.T. Improving the fundamentals of MSn on 2D linear ion traps: new ion activation and isolation techniques. Proc. 53rd ASMS Conference on Mass Spectrometry and Allied Topics, San Antonio, TX, 2005.

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40. Salmon, K.; He, M.; Choudhary, G.; Schwartz, J.; Cho, D. Improved isolation efficiency using higher resolution isolation in an ion trap mass spectrometer. Proc. 54th ASMS Conference on Mass Spectrometry and Allied Topics, Seattle, WA, 2006. 41. Wells, G.J. Quadrupole Trap Improved Technique for Collisional Induced Disassociation for MS/MS Process, US Patent 1994, 5,302,826. 42. Jackson, G.P.; Hyland, J.J.; Laskay, U.A. Energetics and efficiences of collision-induced dissociation achieved during the mass acquisition scan in a quadrupole ion trap. Rapid Commun. Mass Spectrom. 2005, 19, 3555–3563. 43. Schwartz, J.C.; Taylor, D.M. Method of Ion Fragmentation in a Quadrupole Ion Trap, US Patent 2000, 6,124,591. 44. Mulholland, J.J.; Yost, R.A. Multi-level CID: a novel approach for improving MS/MS on the quadrupole ion trap. Proc. 47th ASMS Conference on Mass Spectrometry and Allied Topics, Dallas, TX, 1999. 45. Salmon, K.; Choudhary, G.; Schwartz, J.; Cho, D. Enhanced fragmentation of small molecules in a linear ion trap mass spectrometer using stepped normalized collision energy. Proc. 53rd ASMS Conference on Mass Spectrometry and Allied Topics, San Antonio, TX, 2005. 46. Brekenfeld, A.; Schubert, M.; Franzen, J. Fragmentation in Quadrupole Ion Trap Mass Spectrometers, US Patent 2002, 6,410,913. 47. Goodley, P.C. Technical Note, 5988-0704EN, 2000, Agilent Technologies. 48. Wang, M. Chemical Structure Insensitive Method and Apparatus for Dissociating Ions, US patent application, publication pending. 49. Cunningham, C., Jr.; Glish, G.L.; Burinsky, D.J. High amplitude short time excitation: a method to form and detect low mass product ions in a quadrupole ion trap mass spectrometer. J. Am. Soc. Mass Spectrom. 2006, 17, 81–84. 50. Schwartz, J.C. High-Q Pulsed Fragmentation in Ion Trap, US Patent 2005, 6,949,743. 51. SW-846, Method 8270D, Test Methods for Evaluating Solid Waste, Physical/Chemical Methods, available from: National Technical Information Services, US Department of Commerce, 5285 Port Royal Road, Springfield, VA 22161. 52. SDWA: Safe Drinking Water Act, EPA 816-F-04-030, June 2004, “Understanding the Safe Drinking Water Act”. 53. 525.2 Methods for the Determination of Organic Compounds in Drinking WaterSupplement III (EPA/600/R-95-131). Citation Information Methods for the Determination of Organic Compounds in Drinking Water-Supplement III (EPA/600/R-95-131). This document is available through NTIS (http://www.ntis.gov). Alternatively, the methods from this source can be found on the following CD-ROM: EPA Methods and Guidance for Analysis of Water, Version 2.0. 54. EPA Method Guidance CD-ROM (includes MCAWW Methods, and most current EPA Methods) Citation Information EPA Methods and Guidance for Analysis of Water, Version 2.0 ’ This CD-ROM includes all EPA wastewater test methods approved at 40 CFR 136, all EPA drinking water test methods approved at 40 CFR 141, and various EPA guidance documents related to EPA’s wastewater and drinking water programs. New and revised EPA OW methods and guidance documents will be added to the CD-ROM during periodic updates. Web at: http://www.ntis.gov/product/environmental-test-methods.htm 55. Price, E.K.; Prakash, B.; Domino, M.M.; Pepich, B.V.; Munch, D.J. 2005, Determination of selected pesticides and flame retardants in drinking water by solid phase extraction and capillary column gas chromatography/mass spectrometry: U.S. Environmental Protection Agency Report EPA/815/R-05/005, Version 1.0. 56. Methods for the Determination of Organic and Inorganic Compounds in Drinking Water, Volume 1 (EPA/815-R-00-014) Citation Information Available through: NSCEP Item # 815-R-00-014, (800) 490-9198 or (513) 489-8190 or order from the Web at: http://www. epa.gov/ncepihom/

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57. Munch, J.W. Revision 1.0, Sept. 2002, NERL Method 529: Determination of Explosives and Related Compounds in Drinking Water by Solid Phase Extraction and Capillary Column Gas Chromatography/Mass Spectrometry (GC/MS). 58. Munch, J.W. Revision 1.0, Sept. 2004, NERL Method 521: Determination of Nitrosamines in Drinking Water by Solid Phase Extraction and Capillary Column Gas Chromatography with Large Volume Injection and Chemical Ionization Tandem Mass Spectrometry (MS/MS). 59. SW-846, Method 8270D, Test Methods for Evaluating Solid Waste, Physical/Chemical Methods, available from: National Technical Information Services, US Department of Commerce, 5285 Port Royal Road, Springfield, VA 22161 60. Anastassiades, M.; Lehotay, S.J.; Stajnbaher, D.; Schenck, F. Fast and easy multiresidue method employing acetonitrile extraction/ partitioning and dispersive solid phase extraction for the determination of pesticide residues in produce. (QuEChERS method). J. AOAC Int. 2003, 86, 412–431. 61. The Directive on the Restriction of the Use of Certain Hazardous Substances in Electrical and Electronic Equipment 2002/95/EC[1] http://eur-lex.europa.eu/LexUriServ/Lex UriServ.do?uri = OJ:L:2003:037:0019:0023:EN:PDF 62. Lijinsky, W.; Epstein, S.S. Nitrosamines as Environmental Carcinogens. Eppley Institute for Research in Cancer, University of Nebraska College of Medicine, www.nature.com/ nature/journal/v225/n5227/abs/225021a0.html 63. Tanabe, S. PCB Problems in the Future: Foresight from Current Knowledge. Environ. Pollut. 1988. 50, 5–28. 64. Method 505: Analysis of Organohalide Pesticides and Commercial Polychlorinated Biphenyls (PCB) Products in Water by Microextraction and Gas Chromatography, Winfield, T.W.; Munch, J.W. 1995. National Environmental Research Laboratories, Office of Research and Development, USEPA, Cincinnati, OH 45268. 65. Method 505: Analysis of Organohalide Pesticides and Commercial Polychlorinated Biphenyls (PCB) Products in Water by Microextraction and Gas Chromatography, Winfield, T.W.; Munch, J.W. 1995, pp.18–19. Note: EPA Method 505 from: Methods for the Determination of Organic Compounds in Drinking Water-Supplement III (EPA/600/R-95-131). This document is available through NTIS (http://www.ntis.gov). Alternatively, the methods from this source can be found on the following CD-ROM: EPA Methods and Guidance for Analysis of Water, Version 2.0.

Monitoring 16 Remote of Volatile Organic Compounds in Water by Membrane Inlet Mass Spectrometry Romina Pozzi, Paola Bocchini, Francesca Pinelli, and Guido C. Galletti Contents 16.1 Introduction................................................................................................. 492 16.2 Membrane Inlet Mass Spectrometry (MIMS)............................................. 493 16.3 Membrane Inlet Mass Spectrometry (MIMS) Instrumentation for Prolonged Monitoring.................................................................................. 494 16.3.1 Experimental................................................................................. 494 16.3.2 Laboratory Tests............................................................................ 496 16.3.3 Field Tests...................................................................................... 496 16.4 Results and Discussion................................................................................ 497 16.4.1 Laboratory Tests............................................................................ 497 16.4.1.1 Detection Limits (LOD)................................................ 497 16.4.1.2 Reproducibility............................................................. 498 16.4.1.3 Linearity........................................................................ 498 16.4.1.4 Matrix Effects............................................................... 499 16.4.2 Case Studies................................................................................... 499 16.4.2.1 Acrylonitrile.................................................................. 499 16.4.2.2 Comparison of MIMS with Purge-and-Trap (P&T)/Gas Chromatography (GC)/ Mass Spectrometry (MS)..............................................500 16.4.3 Field Tests...................................................................................... 502 16.5 Conclusion................................................................................................... 505 References...............................................................................................................506

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16.1  INTRODUCTION European Union Directive 98/83 underlines the importance of determining the quality of drinking water in order to protect human health. In particular, a number of chemical compounds are listed, such as benzene, 1,2-dichloroethane, tetrachloroethylene, chloroform, and trihalomethanes, whose concentration in drinking water must be kept under well-defined thresholds. In Italy, laws DL 31/01, DM 152/99, and DM 471/99 set the norms for the concentrations of these, and of many other compounds in drinking water, wastewater, and contaminated sites, respectively. Volatile Organic Compounds (VOCs) constitute a very important class of water pollutants because of their persistence; in addition, many of them are suspected of being carcinogenic. There are about 60 VOCs, including benzene, toluene, ethylbenzene, and xylenes (‘BTEX compounds’), halomethanes, and haloethanes. The presence of some of them in water is due to anthropic activities, for example, the use of chlorinated solvents in industries and laundries, and the formation of halomethanes as by-products of water disinfectants. With respect to Italian law DL 31/01, the maximum allowable concentration (threshold) for the sum of trichloroethylene and tetrachloroethylene concentrations in drinking water is 10 ppb, whereas the minimum account for the sum of a set of four halogenated compounds, namely chloroform, bromoform, bromodichloromethane, and chlorodibromomethane must be as low as possible and must not exceed 30 ppb. Note that 30 ppb is equivalent to 30 μg L –1. A real-time, on-line, continuous monitoring system for such compounds would allow either prompt actions to be taken in order to avoid the diffusion of pollutants into the water system or to take appropriate countermeasures, thus restoring safe conditions in the case of accidental contamination. In general, only the conventional chemical-physical parameters, such as dissolved oxygen temperature, pH, conductivity, and turbidity, are monitored continuously in water [1]. VOCs are usually analysed in the laboratory by means of Purge and Trap/Gas Chromatography/ Mass Spectrometry (P&T/GC/MS) using the U.S. Environmental Protection Agency (USEPA) Method No. 8260B which sets the standard for the analysis of VOCs in water. Although the method is state-of-the-art in terms of sensitivity, reproducibility, validation of the overall procedure and has been adopted worldwide by water laboratories, it can by no means be considered an alarm tool giving rapid warning of concentration increases. For an analytical procedure to be considered a warning device, it should be rapid, simple, and able to work unattended 24-hours-a-day for several days in unmanned sites and to send remotely analytical reports. As appropriately stated by Mikkelsen and coworkers, reporting upon a robust and sensitive on-line remote monitoring system for heavy metals in natural waters, “it is a great distance from developing a method (…) for continuous outdoor measurements” [2]. To our knowledge, little research has been made on the use of the ion trap for continuous, on-line monitoring of environmental parameters. Masuyoshi Yamada et al. studied a continuous monitoring system for the determination of polychlorinated biphenyls in air; the system employed direct sampling atmospheric pressure chemical ionization (APCI)/ion trap mass spectrometry (ITMS) [3]. Direct sampling ion trap mass spectrometers with two direct sampling interfaces, developed at Oak Ridge National Laboratory, TN, USA,

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have been tested in field studies to determine VOCs in the effluents from hazardouswaste incinerators [4]. Kurten et al. developed an ion trap mass spectrometer for the on-line chemical analysis of atmospheric aerosol particles [5].

16.2  MEMBRANE INLET MASS SPECTROMETRY (MIMS) Riter et al. applied Membrane Inlet Mass Spectrometry (MIMS) coupled to a miniature mass spectrometer equipped with a cylindrical ion trap (CIT) analyzer to monitor the flavor components directly from human breath [6]. Johnson et al. measured ethanol concentrations on-line in fermentation broths from a 9000-L fermentation reactor for a period of four days [7]. However, data reported in the above papers referred to experiments lasting no more than a few days. MIMS has been extensively studied for the determination of VOCs in various environmental matrices, especially water and air samples [8–16]. Ketola and coworkers published a review that listed 172 references of MIMS applications to water and air [17]. MIMS allows the introduction of VOCs to the mass spectrometer through a thin (some tenths of a millimeter) hollow-fiber polymeric membrane, which is selective toward organic compounds. When the membrane is in contact with the sample and an ion trap mass spectrometer is used as the detector, such as in the case here, VOCs are extracted into the membrane, concentrated in its small volume, and swept into the mass spectrometer by a gentle stream of helium carrier gas. The whole process is called pervaporation and is divided into three steps: (a) phase-partitioning equilibrium of the organic compound between the sample (water or air) and the membrane; (b) diffusion of the compound by a concentration gradient from the outer side of the membrane (in contact with the sample) to the inner side (connected to the mass spectrometer); and (c) evaporation of the compound from the inner side of the membrane [18]. Diffusion is the rate-determining step, whereas partitioning and evaporation can be considered to be instantaneous. When the membrane is exposed to a sample containing the target compounds and the ions characteristic of each target compound are detected by mass spectrometry, the inherent ion current increases up to a plateau showing that the analyte’s pervaporation rate and transport flow to the detector are equal. The pervaporation process can be described by the Fick’s equations of diffusion [18], that is,

 ∂ Cm ( x , t )  I m ( x , t ) = − AD    ∂ x 

(16.1),



 ∂ Cm ( x , t )   ∂ 2C m ( x , t )   = D     ∂ t  ∂ x2 

(16.2)

where: Im = analyte flow through the membrane (mol s–1); Cm = concentration of the analyte in the membrane wall (mol cm–3); A = membrane surface (cm2); D = diffusion coefficient (cm2 s–1);

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x = membrane thickness (cm); t = time (s). The characteristic ions are the qualitative information which allows identification of the analytes, while plateau height (Iss = ADCm /L, where Iss is the analyte flow and L is the membrane thickness) is the quantitative information, with sensitivity in the sub-ppb levels and dynamic range of up to four decades for many VOCs [17,19].

16.3 MEMBRANE INLET MASS SPECTROMETRY (MIMS) INSTRUMENTATION FOR PROLONGED MONITORING Although the many papers cited above have demonstrated that MIMS is a potentially excellent technique for continuous VOC monitoring given its simplicity and sensitivity, to our knowledge no account has been published of experimental attempts to demonstrate that MIMS can really be implemented in a device able to work unattended for months. Following our previous paper on MIMS upgrades [19], this present work reports on laboratory and field tests of hardware and software for MIMS instruments built in our laboratory. Four instruments were deployed in unmanned sites, where they monitored VOCs in natural waters and wastewater during a period exceeding one year for each instrument. The instruments were equipped with software that facilitated the automatic operation of each analysis, the identification and quantitation of VOCs from the raw mass spectra, and the transmission of the results to a remote control room via internet connection. In the remote control room, a personal computer with dedicated software displayed the results as bar graphs and was programed to activate alarms when set concentration thresholds were exceeded. Laboratory performance in terms of sensitivity, reproducibility, linearity tests, and comparison with P&T/GC/MS together with field performance in terms of data output, most frequent maintenance operations and technical failures, and overall stability of the four remotely-controlled instruments are discussed.

16.3.1 Experimental Table 16.1 lists the VOCs used in the present study together with their respective characteristic ions. All compounds were purchased from Sigma-Aldrich (St Louis, MO, USA). The MIMS system (Analytical Research Systems, Bologna, Italy) was equipped with a helium carrier gas cylinder (chromatography grade, SIAD, Milan, Italy), pressure regulator and a 30 m column with no stationary phase to provide a constant gas flow (1 mL min–1), sample cell, and hollow fiber membrane connected to a quadrupole ion trap mass spectrometer (Varian Inc., Walnut Creek, USA) through a fused silica column (0.32 mm ID, 5 m, Supelco) without a stationary phase. All mass spectra were acquired (5 min) from m/z 50 to 200 at a rate of 1 spectrum/5 s. The trap temperature was 170°C. The sample was kept under magnetic stirring at room temperature during the analysis. Each instrument had five sample inlets so that up to five different water streams could be analyzed. During normal operating conditions, two inlets were dedicated to blank water and calibration solutions, respectively. The device was operated by means of proprietary software able to set: (a) sampling, analytical, and data-transmission functions; (b) identification and

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Benzene Toluene Ethylbenzene Cumene Styrene 1,4-dichlorobenzene 1,2-dichlorobenzene Chloroform Trichloroethylene Tetrachloroethylene Carbon tetrachloride Bromoform Dibromochloromethane Dichlorobromomethane 1,1,1-Trichloroethane Acrylonitrile

Compound

78 91 91 + 106 77 + 105 + 120 78 + 104 146 + 148 + 150 146 + 148 + 150 83 130 + 132 164 + 166 117 + 119 173 129 83 96 + 97 52

Characteristic Ions (m/z) 0.05 0.3 0.1 9 0.2 0.2 0.2 0.03 0.03 0.08 0.1 0.20 0.1 0.1 0.09 40

LOD

MIMS

7 9 9 9 6 5 5 6 4 8 16 19 9 6 10 11

SD% 0.9996 0.9998 0.9998 0.9087 0.9922 0.9986 0.9986 0.9977 0.9984 0.9994 0.9965 0.9927 0.9986 0.9964 0.9982 1.0000

R2 0.25 0.25 0.1 0.25 0.5 0.5 0.5 0.13 0.5 0.5 1 0.5 0.5 0.5 0.5 /

LOD 3 5 6 6 6 6 6 4 4 7 5 8 5 7 7 /

SD%

P&T/GC/MS

0.9989 0.9949 0.996 0.9975 0.9981 0.9878 0.9878 0.998 0.9966 0.9951 0.9917 0.9969 0.9979 0.9977 0.9967 /

R2

0.2 0.55 0.3 0.75 0.2 0.15 0.15 0.15 0.95 0.7 1.05 0.6 0.25 0.4 0.4 /

LOD

USEPA 8260B

Table 16.1 Characteristic ions (m/z); MIMS and P&T/GC/MS Limit of Detection (LOD, ppb), Standard Deviation (SD %), and R2; USEPA Method 8260B LODs (ppb)

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quantification functions; and (c) display and archiving of the results in the remote station. Verification of the status of the device, simple operations related to the control of the mass spectrometer, and checking of the raw results (for example, air/ water checks, tuning, view of the total ion current and mass spectra, etc.) were performed remotely by means of a commercial software package (Laplink Software Inc., Bellevue, WA, USA).

16.3.2 Laboratory Tests Limits of Detection (LOD) were determined by subsequent dilutions of standard solutions down to a signal-to-noise ratio, S/N, of ≥ 3. Signal reproducibility was determined by six replicates of analyte solutions with concentrations ten times larger than the LOD. Finally, linearity was calculated over a concentration range extending from the LOD to 20–100 times the LOD values. All analyses were ­performed with solutions freshly prepared immediately before use by ­appropriate dilution of mother solutions with organic-free triply-distilled water. In turn, mother solutions were prepared daily by dilutions of concentrated solutions of the analytes in methanol stored in a refrigerator except during the daily preparation of solutions. MIMS results were compared to those obtained by USEPA Method 8260B based on P&T/GC/MS. A Tekmar Velocity XPT Purge and Trap (Teledyne Tekmar, Mason, OH, USA) coupled to a Varian Star 3400X Saturn 2000 GC/MS (Varian, Palo Alto, CA, USA) was used under the following conditions: P&T Sample volume: 5 mL; Trap: Supelco Trap E (SP 2100/Tenax/Silica gel/Charcoal); Purge temperature: 30°C; Purge time: 11 min; Purge flow: 40 mL min−1; Desorbing temperature: 180°C; Desorbing time: 4 min; Desorbing flow: 300 mL min−1; Bake temperature: 180°C; Bake time: 10 min; Bake flow: 400 mL min−1; Transfer-line temperature: 150°C. GC/MS Column: Supelco SPB 624, 60 m x 0.32 mm ID, 1.8 µm film thickness; Injector temperature: 125°C; Oven temperature: from 35 to 50°C at 4°C min–1 holding the initial temperature   for 2 min; then to 220°C at 10°C min–1 holding the final temperature for 10 min; Mass spectra: m/z 25–300 at 1 scan min–1.

16.3.3 Field Tests Four MIMS instruments were deployed for field tests in plants that produced water: one instrument was deployed in each of two plants that produced drinking water from

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Table 16.2 MIMS Performance in Field Experiments Field Test Site A B C D

Application Ground Water Potabilization Ground Water Potabilization Surface Water Potabilization Industrial Wastewater Treatment

Total

Days On

Analyses /day

Total Analyses

Days Off

% Off

323

11

3

24

7752

492

24

5

48

23,616

510

37

7

24

12,240

526

20

4

3

1587

1,851

92

5 (aver.)

23 (aver.)

45,195

Note: A tabulation of the operational performance of the MIMS instruments with respect to functional days, non-functional days, the percentage of non-functional days, analyses/day, and total number of analyses for each of four sites.

ground water; one instrument was deployed in a plant that produced drinking water from surface water; and the fourth instrument was deployed in a plant for the treatment of industrial waters. All the plants were located in the area near Bologna. The instruments were programed to sample and to analyze water (analysis duration: 5 min; 1 scan per five seconds full scan of the mass range: m/z 50–200) with the frequency of analysis ranging from three analyses per day to two analyses per hour. Instrument performances were checked over a period ranging from 323 to 526 days (Table 16.2).

16.4  RESULTS AND DISCUSSION 16.4.1 Laboratory Tests The compounds used for the present study were chosen on the basis of the following criteria: halomethanes and haloethanes (compounds 8–15 in Table 16.1) are solvents and disinfection by-products; for compounds 8 and 2–4, the sum of the concentrations in drinking water must be less than 30 µg L –1 whereas for compounds 9 and 10, the threshold is 10 µg L –1; the remaining compounds (compounds 1–7 and acrylonitrile, Table 16.1) are of interest because they are often found in industrial wastewaters such as were used for the present study. 16.4.1.1  Detection Limits (LOD) MIMS detection limits (LOD, S/N ≥ 3) were determined by analysis of reference solutions and were compared with (a) LODs obtained by P&T/GC/MS operated as described in the previous section, and (b) LODs reported by USEPA Method 8260B (Table 16.1). MIMS LODs were (a) smaller than those obtained by P&T/GC/MS for the organohalogen compounds and for benzene by about, in some cases, one order of magnitude; (b) comparable to the other technique for toluene, ethylbenzene, styrene,

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Practical Aspects of Trapped Ion Mass Spectrometry, Volume V

250

Counts

200 150

0.03 ppb

100 50 0 10

20

30

40 50 Minutes

60

70

80

90

FIGURE 16.1  A typical example of a temporal trace of the ion current for m/z 130-132 from trichlorethylene at a concentration of 0.03 ppb, showing the signal intensity and S/N ratio at the detection limit.

and for the two dichlorobenzene isomers (compounds 6 and 7); and (c) markedly higher for cumene. Acrylonitrile showed a high LOD probably due to its poor partitioning equilibrium in the membrane that, in turn, can be ascribed to its relatively high polarity. USEPA Method 603 reports 0.5 ppb as the detection limit for acrylonitrile, using Purge and Trap and gas chromatography with either a Porapak or a Chromosorb 101 packed column. Figure 16.1 shows the ion current (m/z 130–132) of a 0.03 ppb solution of trichloroethylene as a typical example of the signal intensity and S/N ratio at the detection limit. 16.4.1.2  Reproducibility The reproducibility (six replicates) of MIMS’ responses was compared to that obtained by the reference method. The results (expressed as standard deviation percentage, SD%, Table 16.1) were comparable for the two methods, with the exception of carbon tetrachloride and bromoform, whose MIMS standard deviations were greater than those obtained by P&T/GC/MS. The standard deviation percentage for compounds of relatively high polarity and/or low volatility (such as toluene, ethylbenzene, cumene, bromoform, and carbon tetrachloride) was relatively higher than that obtained by P&T/GC/MS; these results probably indicate an unfavorable partitioning equilibrium for these particular compounds in the membrane. 16.4.1.3  Linearity With respect to linearity (Table 16.1), MIMS and P&T/GC/MS were comparable (R2 > 0.99), with the exception of cumene, whose MIMS R2 was 0.9087, probably

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Remote Monitoring of Volatile Organic Compounds in Water

due to the previously-mentioned lower partitioning equilibrium of this compound in the membrane; this observation was consistent with the high detection limit of this compound. Acrylonitrile (Figure 16.2) showed perfect linearity over the 50–750 ppb concentration range. 16.4.1.4  Matrix Effects Standard additions of BTEXs to industrial wastewaters showed no matrix effect. The angular coefficient of the straight line obtained by four additions in the 0.1–2 ppm range was practically identical to that of a similar calibration plot using triplydistilled water (18,954 vs 18,883), the two lines being parallel (Figure 16.3).

16.4.2 Case Studies 16.4.2.1  Acrylonitrile Acrylonitrile, a compound that is not included in the family of the VOCs, could be determined at high concentration levels (4.78 ppm) in industrial waters containing

kCounts

2.0

Ione: 52

750 ppb 500 ppb

1.5 1.0

200 ppb

0.5

50 ppb

100 ppb

0.0 25

50

Minutes

75

100

125

FIGURE 16.2  The m/z 52 ion current for acrylonitrile showed perfect linearity over the 50–750 ppb concentration range. 50,000 Signal

40,000 30,000 20,000 10,000 0

0

0.5

1

ppm

1.5

2

2.5

FIGURE 16.3  Calibration of BTEXs in triply-distilled (continuous line, y = 18,883x + 115.59, R2 = 1) and industrial water (dotted line, y = 18,954x + 7002.1, R2 = 0.9977).

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Practical Aspects of Trapped Ion Mass Spectrometry, Volume V

a wide range of aromatic hydrocarbons. Figure 16.4 shows a MIMS full scan mass spectrum with ions at m/z 78, 104, 91, 120, 121 and 118 (typical of such aromatic substances as styrene, ethylbenzene, xylene, cumene, cumene hydroperoxide, α-methylstyrene) along with an ion at m/z 52 (acrylonitrile) of much lower ion signal intensity, whose ion currents for duplicate analyses are shown in Figure 16.5. 16.4.2.2 Comparison of Membrane Inlet Mass Spectrometry (MIMS) with Purge-and-Trap/Gas Chromatography (GC)/ Mass Chromatography (MS) A series of experiments was performed in order to compare MIMS and Head-Space Purge and Trap /GC/MS by analyzing a total of 20 industrial wastewater samples from seven different sampling points. In Figure 16.6 is shown the MIMS mass spectrum of one of the wastewater samples; in this example, seven compounds that

104

Relative intensity

100%

75%

50% 91

25% 51

63

119

78

0% 50

100

134

155 165 179 150 m/z

205 219 200

FIGURE 16.4  Full scan mass spectrum of a sample of industrial waters containing acrylonitrile (m/z 52) along with aromatic substances such as styrene, ethylbenzene, xylene, cumene, cumene hydroperoxide, and α-methylstyrene.

kCounts

25 20 15 10 5 25

Minutes

50

FIGURE 16.5  Ion current of m/z 52, acrylonitrile at 4.78 ppm, duplicate analysis of the same sample of industrial waters as was used for Figure 16.4.

50

55

65 61

60

66

75

Chloroform

79

83

100

105

Toluene 91 101 1,2 dichloroethylene 96 CCl4 117 98

125 m/z

130

134

Trichloroethylene 132

150

151

175

Tetrachloroethylene 166

200

FIGURE 16.6  Mass spectrum of industrial water used to compare MIMS and Purge-and-Trap/GC/MS. Identified compounds and ions used for quantification are reported.

0%

25%

50%

75%

100%

Remote Monitoring of Volatile Organic Compounds in Water 501

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Practical Aspects of Trapped Ion Mass Spectrometry, Volume V 30,00

y = 1,0671x – 0,6296 R 2 = 0,8944

ppb (P&T/GC/MS)

25,00 20,00 15,00 10,00 5,00 0,00

0

–5,00

5

10

15

20

25

ppb (MIMS)

FIGURE 16.7  Comparison of data obtained by analyzing samples with Purge-and-Trap/ GC/MS and MIMS. The concentration (in ppb) of each of toluene (m/z 91), benzene (m/z 78), 1,2-dichloroethylene (m/z 98), trichloroethylene (m/z 130 + 132), chloroform (m/z 83), and vinyl chloride and dichloroethane (m/z 62 for both compounds) in each of 20 wastewater ­samples determined by MIMS is plotted against that determined by Purge-and-Trap/GC/MS.

have been identified by their characteristic ions are indicated on the mass spectrum. Toluene (m/z 91), benzene (m/z 78), 1,2-dichloroethylene (m/z 98), trichloroethylene (m/z 130 + 132), chloroform (m/z 83), and vinyl chloride and dichloroethane (m/z 62 for both compounds) were detected and quantified in all 20 samples with both techniques. The concentration (in ppb) of each of the above seven compounds in each of 20 wastewater samples determined by MIMS is plotted against that determined by P&T/GC/MS as shown in Figure 16.7. The equation of the regression line calculated from these data (Figure 16.7) is y = 1.0671x–0.6296, R2 = 0.8944. The slight differences between the actual and the ideal coefficients (slope = 1, intercept = 0 and R2 = 1) are probably due to the contributions of other compounds to the abundances of the ions used for quantitation.

16.4.3 Field Tests Four instruments were deployed in different plants representative of typical cases of water treatment, namely two plants for the potabilization of ground water (A and B), the third plant for surface water potabilization (C), and, finally, a plant for industrial water treatments (D) (Table 16.2). In field test A, the instrument was deployed in a plant for the production of drinking water from ground water using chlorine dioxide as a disinfection agent. Due to past industrial activity in that area, the ground water was heavily contaminated by chloroform and trichloroethylene. Charcoal filters were used to abate the organohalogen concentration in drinking water down to 1–10 ppb levels. The instrument was located in a 2 × 3 m container maintained at room temperature. The instrument was able to identify and to quantify drinking water pollutants by means of a mass spectrum in which the ions characteristic of the individual compounds were recorded clearly, showing their

Remote Monitoring of Volatile Organic Compounds in Water

503

respective diagnostic isotopic patterns (Figure 16.8a). Hourly analyses were carried out in order to check that pollutant concentrations did not exceed the legal thresholds. The position was unmanned and the results were transmitted to the remote control room by e-mail at the conclusion of each analysis. The instrument was monitored over a period of 334 days during which it functioned for 323 days; failures and maintenance resulted in the loss of 11 days (that is, 3% of the time monitored) (Table 16.2). Almost 8000 determinations were performed corresponding to 646 hours of analysis. In plant B, both ground water and drinking water were monitored every hour, corresponding to a total frequency of one analysis per 30 minutes. Here, the contaminant was trichloroethylene. The plant was not equipped with charcoal filters, consequently the pollutant concentration was kept within the regulation limit (10 ppb) by shifting water uptake from one well to another. Figure 16.8b shows a typical full-scan mass spectrum recorded from the ground water of this location, with the characteristic trichloroethylene molecular ion isotopic quartet at m/z 130, 132, 134, and 136. As for the previous field study in plant A, the location was unmanned and the results were transmitted by e-mail. The percentage of inactivity in plant B (5%) was comparable with that of plant A (3%), despite the fact that the working period for plant B (almost 500 days) was longer than that for plant A, and the number of analyses carried out at plant B (23,626) was more than three times higher than those carried out in plant A (7,752); see Table 16.2. Field test C was an example of application to surface waters used for human consumption. Such waters were essentially uncontaminated by chemicals and needed only a conventional disinfection. Nevertheless, this plant was monitored in consideration of the fact that accidental pollution by gasoline and oil had been recorded in the past due to the proximity of an adjacent highway with heavy traffic. Figure 16.8c shows a typical mass spectrum of this instance, with no significant ions. This instrument was monitored over 547 days (12,240 analyses, 1020 hours) during which the days off were 37, that is 7% of the period (Table 16.2). Finally, industrial wastewaters (plant D) were analyzed from the outlet of a pipe connected into a municipal sewage treatment plant. In such a case, the concern was that organohalogenated compounds from industrial wastes may affect the biological treatment of urban wastewaters. The instrument recorded 3 analyses per day on those days when the industrial wastewaters were discharged. Figure 16.8d shows the typical mass spectrum of such samples. Ions characteristic of chloroform (m/z 83, 0.3 ppb), trichloroethylene (m/z 130, 23 ppb), and toluene (m/z 91, 31 ppb) were found in the mass spectrum reported in Figure 16.8d. The complex matrix of such wastes did not affect the MIMS determinations (see previous discussion, Figure 16.3). The instrument was monitored during more than 500 days (about 1600 analyses or 130 functioning hours) with a 4% of non-functioning time (Table 16.2). For all types of mass spectrometers, particularly those operated in remote locations, it is of interest to consider the frequency of mass calibration and, for those instruments that employ electron impact ionization, the frequency with which the filament must be replaced. It was found for the MIMS instruments that mass calibrations were carried out on 24 occasions and filaments were replaced on 16 occasions.

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Practical Aspects of Trapped Ion Mass Spectrometry, Volume V

(a) 100%

164

75% Chloroform 94 96 83

50% 25%

166 Tetrachloroethylene 168

0% 50

75

100

(b) 100%

m/z

125

150

175

130 132

75% Trichloroethylene

60

50% 25%

96

134

100

150 m/z

0% 50 (c)

100%

250

45 52

75% 50%

200

41

25% 0% 50

75

100

(d)

125 m/z

150

175

200

91 Toluene

100% 75% 50%

Chloroform

25%

77 83

105

Trichloroethylene 130 132

0% 50

100

m/z

150

200

Remote Monitoring of Volatile Organic Compounds in Water

505

FIGURE 16.8  (Opposite) (a) Field test A. Mass spectrum of a water sample from a plant for the production of drinking water from ground water. Chlorine dioxide had been used as a disinfection agent. Ground water was contaminated heavily by chloroform and trichloroethylene due to past industrial activity; charcoal filters had been used to abate the organohalogen concentration in drinking water down to 1–10 ppb levels. (b) Field test B. Mass spectrum recorded from the ground water of this location. At this site, the contaminant was trichloroethylene and the mass spectrum shows the characteristic trichloroethylene molecular ion isotopic quartet at m/z 130, 132, 134, and 136. The plant was not equipped with charcoal filters, consequently pollutant concentration was kept within the regulation limit (10 ppb) by shifting water uptake from one well to another. (c) Field test C. Mass spectrum of surficial water used for human consumption. Such waters were essentially uncontaminated by chemicals and needed only a conventional disinfection. No significant ions were observed. (d) Field test D. Mass spectrum of a sample of industrial wastewaters taken from the outlet of a pipe connected into a municipal sewage treatment plant. In this case, the concern was that organohalogenated compounds from industrial wastes may affect the biological treatment of urban wastewaters. This typical mass spectrum shows ions characteristic of chloroform (m/z 83, 0.3 ppb), trichloroethylene (m/z 130, 23 ppb), and toluene (m/z 91, 31 ppb).

From the data shown in Table 16.2 concerning the numbers of operating days and the number of analyses carried out each day at each of the four sites, it is found that averages of 2825 analyses were carried out with each filament and 1883 analyses were carried out between successive calibrations. Comparing these data with those of a GC/MS instrument used presently in our laboratory and which has shown good instrumental stability and reliability, it was found that the GC/MS instrument performed 305 analyses per filament and 78 analyses per calibration. When it is borne in mind that the duration of a GC/MS analysis was 50 min while that of a MIMS analysis was 5 min, it is clear that both systems performed comparably in terms of operation time per filament.

16.5  CONCLUSION A number of laboratory tests to determine LOD, linearity and repeatability of MIMS instruments applied to the analysis of VOCs in water were performed. Data were comparable with those obtained by the classical method of VOC analysis in water (P&T/GC/MS and USEPA Method 8260B). Four MIMS instruments were tested over an extensive period of time to evaluate their on-site performance in unmanned locations. Results were remarkable: the instruments worked unchecked for long periods producing a total of more than 45.000 analyses and VOC amounts were quantified automatically and sent to a remote control room where non-expert personnel could understand the results readily. In conclusion, MIMS instruments proved to have great potential for utilization in continuous VOC-monitoring stations. These instruments are reliable, cost-effective and simple to use; they have no environmental impact because no solvent is used for the extraction of organics from water, and they can be located on-site, unattended, providing a continuous flow of data on water quality and pollution.

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Practical Aspects of Trapped Ion Mass Spectrometry, Volume V

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1. Irvine, K.N.; McCorkhill, G.; Caruso, J. Continuous monitoring of conventional parameters to assess receiving water quality in support of combined sewer overflow abatement plans. Water Environ. Res. 2005, 77, 543–552. 2. Mikkelsen, Ø.; Skogvold, S.M.; Schrøder, K.H. Continuous heavy metal monitoring system for application in river and seawater. Electroanalysis 2005, 17, 431–439. 3. Yamada, M.; Suga, M.; Waki, I.; Sakamoto, M.; Morita, M. Continuous monitoring of polychlorinated biphenyls in air using direct sampling APCI/ITMS. Int. J. Mass Spectrom. 2005, 244, 65–71. 4. Hart, K.J.; Dindal, A.B.; Smith, R.R. Monitoring volatile organic compounds in flue gas using direct sampling ion trap mass spectrometry. Rapid Commun. Mass Spectrom. 1996, 10, 352–360. 5. Kürten, A.; Curtius, J.; Helleisa, F.; Lovejoy, E.R.; Borrmann, S. Development and characterization of an ion trap mass spectrometer for the on-line chemical analysis of atmospheric aerosol particles. Int. J. Mass Spectrom. 2007, 265, 30–39. 6. Riter, L.S.; Laughlin, B.C.; Nikolaev, E.N.; Cooks, R.G. Direct analysis of volatile organic compounds in human breath using a miniaturized cylindrical ion trap mass spectrometer with a membrane inlet. Rapid Commun. Mass Spectrom. 2002, 16, 2370–2373. 7. Johnson, R.C.; Srinivasan, N.; Cooks, R.G.; Schell, D. Membrane introduction mass spectrometry in a pilot plant: On-line monitoring of fermentation broths. Rapid Commun. Mass Spectrom. 1997, 11, 363–367. 8. Bier, M.E.; Cooks, R.G. Membrane interface for selective introduction of volatile compounds directly into the ionization chamber of a mass spectrometer. Anal. Chem. 1987, 59, 597–601. 9. Kotiaho, T.; Lauritsen, F.R.; Choudhury, T.K.; Cooks, R.G.; Tsao, G.T. Membrane introduction mass spectrometry Anal. Chem. 1991, 63, 875A–883A. 10. Lauritsen, F.R.; Kotiaho, T.; Choudhury, T.K.; Cooks, R.G. Direct detection and identification of volatile organic compounds dissolved in organic solvents by reversedphase membrane introduction tandem mass spectrometry. Anal. Chem. 1992, 64, 1205–1211. 11. Bauer, M.; Solyom, D. Determination of volatile organic compounds at the parts per trillion level in complex aqueous matrixes using membrane introduction mass spectrometry. Anal. Chem. 1994, 66, 4422–4431. 12. Soni, M.; Bauer, S.; Amy, J.W.; Wong, P.; Cooks, R.G. Direct determination of organic compounds in water at parts-per-quadrillion levels by membrane introduction mass spectrometry. Anal. Chem. 1995, 67, 1409–1412. 13. Cisper, M.E.; Gil, C.G.; Townsend, L.E.; Hemberger, P.H. Online detection of volatile organic compounds in air at parts-per-trillion levels by membrane introduction mass spectrometry. Anal. Chem. 1995, 67, 1413–1417. 14. Mendes, M.A.; Pimpim, R.S.; Kotiaho, T.; Eberlin, M.N. A cryotrap membrane introduction mass spectrometry system for analysis of volatile organic compounds in water at the low parts-per-trillion level. Anal. Chem. 1996, 68, 3502–3506. 15. Ketola, R.A.; Mansikka,T.; Ojala, M.; Kotiaho, T.; Kostiainen, R. Analysis of volatile organic sulfur compounds in air by membrane inlet mass spectrometry. Anal. Chem. 1997, 69, 4536–4539. 16. Bocchini, P.; Pozzi, R.; Andalò, C.; Galletti, G.C. Membrane inlet mass spectrometry of volatile organohalogen compounds in drinking water. Rapid Commun. Mass Spectrom. 1999, 13, 2049–2053.

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Author Index* Ausio, J., 69 Abedi, A., 408, 409 Adamczyk, M., 88, 90 Amunugama, M., 91 Arriaga, E.A., 99 Back, J.W., 104 Badman, E.R., 8, 17 Baessmann, C., 282 Bagal, D., 227 Bartlet-Jones, M., 98 Bateman, R.H., 210 Berton. A., 367 Bier, M.E., 447 Bisgaard, C.Z., 312 Blatt, R., 359 Blom, M.N., 180 Bocchini, P., 491 Bowers, M.T., 207, 208, 219 Brancia, F.L., 367 Brekenfeld, A., 282 Brittain, R., 445 Brock, A., 140 Brodbelt, J.S., 36, 39, 46–48, 55 Bruce, J.E., 104 Burns, M.M., 180 Bush, M.F., 244, 248, 249 Caldwell, G., 397, 399–402 Carter, J.G., 408 Champenois, C., 333 Chen, X., 103 Chipuk, J.E., 36, 39, 46, 48, 55, 65 Chowdhury, S., 410 Chrisman, P.A., 8, 13 Christophorou, L.G., 408 Chung, S., 354 Clemmer, D.E., 216 Clench, M., 225 Cooks, R.G., 170, 224, 278, 328 Coon, J.J., 10, 22, 59, 63, 65, 69, 71, 72 Cooper, H.J., 121, 207 Cudzilo, K., 434 Danell, R.M., 180 Daniels, S., 98 Dehmelt, H.G., 170, 328, 334 Dey, S., 98 Dick, G.J., 337 Djdja, M.-C., 226

Douglas, D.J., 52, 53, 380, 381 Drewsen, M., 254, 291, 294, 296, 297, 300, 309, 311, 312, 356 Drexler, D.M., 435 Dryhurst, D.D., 69 Duft, D., 189, 190, 193, 194, 196, 197 Dunbar, R.C., 248, 249 Eckers, C., 228 Eiceman, G.A., 206, 387, 404 Erickson, D.E., 13 Evoy, S., 309 Ewing, R.G., 404, 405 Fenn, J., 127 Fico, M., 328 Fitaire, M., 396, 397 Fohlman, J., 131 Forbes, M.W., 239, 248, 249 Franzen, J., 263, 264, 277, 282 Froelich, J.M., 60, 83 Galletti, G.C., 491 Gao, L., 328 Gardner, M.W., 109 Garrett, T.G., 225 Garzón, I.L., 179, 180, 417, 420, 428, 433 Gauthier, J.W., 132 Ge, Y., 144 Gebler, J.C., 90 George III, J.E., 439 Gerlich, D., 245, 335 Gheno, F., 396, 397 Giles, K., 210 Glish, G.L., 6, 70, 465 Goshe, M.B., 105, 106 Grabenauer, M., 219 Griffin, T.J., 99, 100 Grimsrud, E.P., 397, 399–402, 410 Gronert, S., 43 Gunawardena, H.P., 70 Gygi, S.P., 94, 142 Haberland, H., 171 Hakansson, K., 140 Han, H., 23 Han, H.L., 64, 66 Harden, C.S., 404, 405 Hartmer, R., 282 Harvey, D.J., 227 Hattan, S., 98

* The names listed here refer only to authors whose names appear in the text and/or in the captions.

509

510 He, F., 98 Hilton, G.R., 219 Hiraoka, K., 397 Hogan, J.M., 18 Højbjerre, K., 254, 291, 311, 312, 356 Holland, R., 227 Huang, Y.N., 98 Hunt, D.F., 10, 22, 36, 37, 63, 69, 139, 451 Hunter, E.P., 38 Hunter, S.R., 408 Iavarone, A.T., 189, 190 Jackson, G.P., 463 Jacobson, A., 98 Jensen, L., 296, 297 Jockusch, R.A., 239, 248, 249 Johnson, R.C., 493 Juhasz, P., 98 Julien, R.R., 93 Julka, S., 94, 95 Jung, H.R., 228 Kaplan, D., 282 Karpas, Z., 206 Kebarle, P., 395, 402, 410 Ketola, R.A., 493 Khainovski, N., 98 Kiessel, S.E.B., 71, 72 Kim, S.H., 395 Knighton, W.B., 402, 410 Konenkov, N.V., 380, 381 Kürten, A., 493 Landman, U., 181, 182 Laskin, J., 140 Lawless, P.A., 406 Lawrence, A.H., 402 Le, T., 354 Li, L., 85 Li, S., 97 Liang, X.R., 11, 13 Lias, S.G., 38 Lindballe, J., 296, 297 Liu, J., 3, 13, 64 Liu, Y., 408 Londry, F.A., 13 Louris, J.N., 459 Lu, Y., 60, 83 Ly, T., 93 Magnera, T.F., 402 Maleki, L., 337, 340, 354 Manura, D., 273 Mao, D., 52 March, R.E., 350, 440 Marchese, J.N., 98 Margolis, H., 346 Marshall, A.G., 130, 132, 138, 144 Martin, S., 98 Martinussen, R., 294, 296, 297, 300, 309 Mayhew, C.A., 407, 408

Author Index McAlister, G.C., 59, 71, 72 McEwen, C.N., 225 McLean, J.A., 225 McLuckey, S.A., 3, 7, 8, 11, 13, 17, 18, 20, 23, 62, 64, 66–68, 72 Meany, D.L., 98, 99 Michaelian, K., 179, 180 Mikkelsen, Ø., 492 Mordehai, A., 440 Mortensen, A., 294, 296, 297, 300, 309, 312 Mulholland, J.J., 464 Mulligan, C.C., 328 Newton, K.A., 20 Nissen, N., 296, 297 Offenberg, D., 312 Olivova, P., 226 Oomens, J., 248, 249 Ouyang, Z., 328 Pappin, D.J., 98 Paradisi, C., 371 Parker, K., 98 Parks, J.H., 169, 180, 181, 189, 190, 193, 194, 196, 197 Paul, W., 262, 328, 439 Payne, A.H., 70 Peverall, R., 408 Pillai, S., 98 Pinelli, F., 491 Plass, W.R., 275–277 Plet, B., 153 Polfer, N.C., 248, 249 Pozzi, P., 491 Prestage, J.D., 337, 340, 354 Preston, J.M., 396, 398 Przybylski, M., 140 Purkayastha, S., 98 Purves, R.W., 209 Qiu, Y., 96 Rajadhyax, L., 396, 398 Ramsey, N., 332 Raveane, L., 367 Regnier, F., 94, 95 Reich, R.F., 434 Reid, G.E., 17, 60, 83, 91, 100 Reilly, J.P., 252 Riba-Garcia, I., 226 Ridenour, W.B., 225 Rizzo, T.R., 245 Roberts, K.D., 91 Roepstorff, P., 130, 131 Ross, P.L., 98 Rutherford, E., 3 Sadagopan, N., 89 Sahlstrom, K.E., 409, 410 Schmitter, J.-M., 153 Schrama, C.A., 346 Schroeder, M.J., 10, 22, 63

511

Author Index Schubert, M., 282, 440 Schwartz, J.C., 65, 440, 461, 463–465 Scrivens, J.H., 205, 219 Shabanowitz, J., 10, 22, 63, 69 Shi, X., 193, 194, 196, 197 Simon, C., 155, 164 Slade, S.E., 219 Smith, R.D., 132, 138 Soderblom, E.J., 105, 106 Song, Q., 328 SØrensen, J.L., 294, 300, 309 Spangler, G.E., 406 Specht, A., 440 Staanum, P.F., 254, 291, 294, 296, 297, 300, 309, 311, 312, 356 Stapelfeldt, H., 312 Stauber, J., 226 Steinwedel, H., 439 Stephenson J.L., 7, 63, 67, 68 Stick, D., 295 Stone, J.A., 206, 387, 404 Strife, R.J., 449 Sudakov, M., 380, 381 Summerfield, S.G., 89 Swaney, D.L., 64 Syka, J.E.P., 10, 22, 63, 65, 69 Tabrizchi, M., 408, 409 Talbot, F.O., 239 Tanaka, K., 127 Taylor, D.M., 444, 459, 463 Thalassinos, K., 205, 219, 223 Thompson, L.V., 99 Thompson, R.C., 334 Thomson, J.J., 3 Tjoelker, R.L., 340

Todd, J.F.J., 350, 440 Traldi, P., 367 Trim, P.J., 225 Turecek, F., 136 Ueberheibe, B., 69 Uetrecht, C., 221 Vedel, F., 327 Voight, D., 296, 297 Wang, H., 86 Wang, M., 445 Wang, N., 85 Watson, J.T., 89 Wells, G.J., 447, 462 Wells, J.M., 17 Wester, R., 311 Williams, E.R., 248, 249 Williams, J.P., 228 Williamson, B., 98 Wineland, D., 170 Wirtala, M., 65 Wright, P.J., 53 Wu, J., 90 Xia, Y., 11, 23, 62, 66 Xie, H., 99 Xing, X., 180, 181 Yamabe, S.J., 397 Yamada, M., 492 Yang, M., 23, 439 Yang, M.J., 13 Yoon, B., 181, 182 Yost, R.A., 225, 417, 434, 446, 464 Zeng, D., 97 Zhang, J., 47, 53 Zhou, H., 96 Zubarev, R.A., 143

Subject Index 1,4-Dinitrobenzene, 399 1,1,1-Trichloroethane, 496 1,2-Dichloroethylene, 501, 502 1,2-Dichlorobenzene, 495 1,2-Dichloroethane, 492 1,4-Dichlorobenzene, 495 115In +, 359 171Yb +, 345 18O atom, 103 18O −, 71 2 199Hg+, 345, 352, 356 2-(2′-Hydroxybenzoyl)–benzoic acid, 371, 372 2,2′,4,4′,6-Pentabromodiphenylether, 480 2,3-Dichlorobiphenyl, 484, 485 2,3-Dimethyl pyridine, protonated, 391 2,3-Dimethyl-2,3-dinitrobutane, 399, 400 2,3-Dimethyl-2,4-dinitropentane, 399 2,4-Dichlorophenol, 472–474 2,4-Dimethylpyridine, 403–406 2,4-Dinitrofluorobenzene-d 0/d3, 103 2,5-Hydroxybenzoic acid, 425, 428, 429 cluster ion of, 430 2,6-Naphthalic acid, 48 202Hg+, 352 24Mg+, 307, 312, 324 24MgH+, 324 25Mg+, 324 2D Polyacrylamide gel electrophoresis, 2D PAGE, 93 2D Quadrupole ion trap, 417, 419 2-Deoxy-5-cytidine monophosphate, 46 2-Methoxy-4,5-dihydro-1H-imidazole, 88 3-(3-Methoxypropoxy) propanol, 396 3,3′-Dithio-bis(succinimidylpropionate), DTSSP, 104 3D Quadrupole ion trap mass spectrometer, 5, 9, 7, 17, 51, 54, 62, 242, 257, 282, 417, 419, 440 40 Ca +, 300, 305, 307–309, 312–316, 318, 320, 321 40 Ca16O +, 300, 305, 310 42Ca +, 309 44Ca +, 309 4-Sulfophenyl isothiocyanate, 89 5′P-dAA, 55 5′P-Dag, 55 5′P-dGA, 55 5′P-dGG, 55 63Ni source, 207, 390, 395

6-Aza-2-thiothymine, 431, 433 Sr+, 345, 359

88

A Absorption spectroscopy, 240 AC dipole electric field, 440 Accidental contamination, 492 Accurate mass tag, AMT, 129, 140 Acetic acid, 127 Acetone, 396 Acetone–water, 397 Acetonitrile, 127, 155, 481 Acetylacetone, 88 Acid-labile isotope-coded extractants, ALICE, 96 Acquisition phase, 372 Acrylonitrile, 491, 495, 498–500 Acrylonitrile butadiene styrene plastic, ABS, 480, 482 Action spectroscopy, 240, 246, 247, 253, 282 Activated ion electron capture dissociation, AI-ECD, 137 Activation barrier, 371 Activation energy, reverse, 496 Adduct ions, 411 dissociation of, 387, 403 Adiabatic approximation, 349 Adiabatic cooling, 396 Affinity capture method, 86 Affinity tag, 105 Aging, 425 Agn+ cluster, 171, 174, 177, 178–181 Al2O3, 86 Al3+, 86 Alcohol dehydrogenase, 141, 219 Aldolase, 219 Allan deviation, 331 Allan Variance, 331 Alveolar proteomics, 140 cystic fibrosis, 140 proteinosis, 140 Alzheimer’s disease, 220 Ambient pressure, 387, 389 American Society for Mass Spectrometry, 284 Amino acid residue, modification site, 84 Ammonium acetate, 127 Ammonium hydroxide, 127 Amplitude detection, 304, 310, 320

513

514 Amplitude method, 304, 320, 321, 323 Amplitude, modulation frequencydependent, 304 Amyloid fibril, 220 Amyloidogenic protein β2-microglobulin, 220 Analysis, drug, 441 food, 441 forensic, 441 Analytical mass scan, 375, 377 Anharmonic bottleneck, 250 Anharmonicity, 315, 316, 338 Aniline ion (C6H5NH2+), 311 photofragmentation, 311, 312 Anion formation, 408 Anthracene, 452, 453, 455 Anthropic activities, 492 Apigenin, 155, 156, 162, 163 Apigenin-7-O-glucoside, 155, 156, 162, 163 Apigenin-7-O-neohesperidoside, 155, 156, 162, 163 Apomyoglobin, 64 Applied Biosystems peptide synthesizer, 156 Arabidopsis, 65 Arginine, 24, 127, 191, 247–249 Argon, 244, 368 Arrhenius parameters, 410 Arrhenius plot, 405, 409 Arrhenius rate model, 197, 198 Arrival time, 401 corrected, 218 distribution, 212 distribution profile, 214, 217, 223 ASGDI, 6, 7 ASGDI source, 8, 11 Aspartic acid cleavage, 16 Aspartic acid residue, 22 location of, 90 Astragalin, 50 Astronomical time, 329 Atmospheric pressure, 388 chemical ionization, APCI, 8, 12, 492 ion emitter, dual, 63 solids analysis probe, ASAP, 225 Atmospheric sampling glow discharge ionization, see ASGDI Atomic beam, 332, 342 Atomic clock, 327–360 schemes, 332 Atomic fountain, 331, 332 Atomic ion lifetime, 328 Atomic ion, laser-cooled, 292–295, 297, 299, 300, 304, 305, 310, 317, 318, 323 Atomic ions, 170, 299 fluorescence, 170 laser cooling, 170, 328 Atomic laser, 328 Atomic levels, 358

Subject Index Atomic oscillator, 331, 360 Atomic quantum physics, 328 Atomic spectroscopy, high resolution, 328 Atomic transition, 330, 331, 335, 339, 355 Atrazine, 478, 479 Attachment rate coefficients, 407 au, 261 AuCl2−, 70, 175, 176, 182–186 Aun− cluster, isomer structure, 184–186 Automated method development, AMD, 467, 486 Automatic gain control, AGC, 422–425, 444, 467 Auxiliary dipolar AC potential, 272 Auxiliary RF voltage, 9, 11 Average dipole orientation, ADO, 402 Averagine, 129 Aviation security, 129 Avidin affinity chromatography, 97 Axial modulation, 272, 273, 440, 456, 467 az, 261, 270, 298, 350, 369 Azobenzene radical anion, 23 Azulene anion, 410

B Ba+, 345 Backbone cleavage, 24 Background gas, 319, 339 Background noise, 447 BAD, see Boundary-activated dissociation BAPMPS, 92 Barium, 332, 334 Baseline interferometry, 330 Bath gas, 5; see also Buffer gas atomic/molecular weight, 446 helium, 42, 43, 171, 174, 175, 195 neon, 175 pressure, 10 temperature, 191 BDE 100, 481 BDE 153, 481 BDE 154, 481 BDE 183, 481 BDE 205, 481 BDE 209, 480–482 BDE 28, 481 BDE 47, 481 BDE 99, 481 Beaker profile, 335 Benzene, 36, 492, 495, 502 Benzoic acid anions, 68–70 Benzyl cation, 104 Beryllium, 319, 357 Biological molecule, 246 identification, 84, 128 structural characterization, 84, 128

515

Subject Index Biomolecular conformation, 170 Biomolecular ions, 192 trapped, 169 Biomolecule analysis, 15 Biomolecule conformational change, 186 Biomolecule folding, 255 Biomolecule protonated, photo-excitation of, 240 Biomolecule, dye-derivatized, 186–188 Biphenyl, 483, 484 BIRD, see Blackbody infrared radiative dissociation Bisuccinimidyl-succinamyl-aspartyl-proline, SuDP, 106 Bisuccinimidyl-succinamyl-aspartyl-prolylglycine, SuDPG, 106 Black hole (or canyon), 263, 348, 350–352, 353 Blackbody heating, 41 Blackbody infrared radiative dissociation, BIRD, 123, 130, 246, 253 principles, 134 protein and peptide, 134, 135 Blackbody radiation, 41, 332, 359 BMS-X, 435 Body-centered cubic (bcc) symmetry, 177 Boltzmann distribution, 388 Boltzmann sigmoidal function, 158 Boltzmann’s constant, 207 Bottom-up approach, see Proteomics, bottom-up, 101 Boundary activation, 367, 369, 382 Boundary effect, 371 Boundary-activated charge-separation dissociations, 383 Boundary-activated dissociation, 367, 369, 370, 373, 374, 385 Bovine cytochrome c charge states, 218 Bovine serum albumin, 16, 17, 141, 154 Bradykinin, 51, 52, 154 fragment (residues RPPGF), 380, 381 doubly-protonated molecule of, 378, 380, 382–384 Bragg diffraction peak, 177, 178 Brain natriuritic peptide (BNP-32), 140 BrCH2COC6H5, 91 Breakdown curve, 159, 160 Breast carcinoma cell, proteomics analysis of, 140 Breath, human, 493 Breathing (BR) mode, 294, 301–303, 305, 307, 308, 313–316, 322, 323 Brewster angle window, 187 Broad-band frequencies, 369 Bromide ion, 411 Bromodichloromethane, 492 Bromofluorobenzene, 467 Bromoform, 492, 495, 498

Broth, fermentation, 493 Brownian motion, 392 Bruker Daltonics HCTultra, 14 Bruker HCTultra/Agilent 6340 ETD ion trap, 8 Bruker ion trap, 442 BTEX compounds, 492, 499 Buffer gas, 205, 207, 245, 278, 279, 281, 310, 368, 382, 440; see also Bath gas atomic/molecular weight, 446 collision, 335, 354 pressure, 281, 446 Butanedione, 101

C C2D2, 312 C2H5+, 449 C2H5OD, 37 C60 cluster ion, 178, 179 C6D5OD, 38 C6H5CH2OD, 38 Ca+, 295, 299, 318, 349, 350, 355, 358, 359 isotope combination, 309 Cage, miniaturization of, 328 Calcium acetate, 20 Calcium beam, 318 Calibration procedure, 216, 217 California Institute of Technology, 329 Camera, 420 Canada Research Chairs Program, 284 Canadian Foundation for Innovation, 284 Cancer, 418 CaO+, 305 Carbon tetrachloride, 408, 409, 495, 498 Carbonic anhydrase, 133, 138 Carcinogens, 483 Case Studies, 499 Casein, 154 Catechin (+), 49, 155, 156, 162–164 galloylated, 49 non-galloylated, 49 Cation adducts, 421 Cation/anion complex formation, 20 Cationic salts, 421 Cavity ring-down spectroscopy, CRDS, 240, 241 CCD camera, 294, 295, 300, 301, 305, 319–321 image, 180, 310 pixel value, 178 CD3OD, 38, 43, 51–54 Center-of-mass (COM) mode, 294, 301–303, 305, 307–309, 313–316, 319–323 Central barrier, 402 Cerebral peduncle, 425 Cerebrospinal fluid, 85 Cesium atom, 329 Cesium atomic frequency standard, 329, 331, 352

516 CF3CH2OD, 38 CH3OD, 38 CH5+, 449 Champagne flute profile, 335 Charge capacity, 442 extended, 439, 442 ion trap, 444 Charge inversion, 12, 15, 19 reaction, 72 negative-to-positive, 19 positive-to-negative, 19 Charge limit, spectral, 444 Charge reduction, 16 stepwise, 19 Charge state, 15, 17, 19, 67 deconvolution, 70 manipulation, 6, 15, 16 Charge transfer, exothermicity of, 197 photoinduced, 196 Charge-coupled device, CCD, 176, 177 Charge-dependent dissociation, 16 Chemical background, 436 Chemical derivatization, 83, 85, 92 reagent, 101 strategy, 88, 89, 91, 94 fixed-charge, 101 Chemical distributions, intrinsic, 418 Chemical ionization reagents, liquid, see Ionization, chemical, liquid Chemical ionization source, 9–11, 14 Chemical ionization, see CI Chemical ionization, see Ionization, chemical Chemical mass shift, 276 Chemical modification technique, 102 Chemical reaction path, 328 Chemical signature, 418 Chemical structure elucidation, 450 Chemical vapor deposition, CVD, 445 Chemicals Warfare Convention, 229 Chemistry analysis, 328 Chicken egg white proteome, 142 Chloride ion, 400, 401, 403, 406, 407, 410, 411 Chlorine dioxide, disinfection by, 505 Chlorobenzene, 407 Chlorodibromomethane, 492 Chloroform, 408, 492, 495, 501, 502, 504 counter flow of, 398 Chloropyriphos, 477, 478 Choline, 425 Chromatographic separation, 85 Chromatographic timescale, 24 Chromosorb 101, 498 CI, see Ionization, chemical CI/MS/MS, see Ionization, chemical/tandem mass spectrometry CID, see Collision-induced dissociation CID-MS/MS, 88, 100

Subject Index Circular dichroism spectroscopy, 219 Cleavable isobaric labeled affinity tag, CILAT, 97 CLIO, 247 Clock atomic transition, 360 Clock signal, 330, 331, 339 building, 341 Clock transition, 343 Cluster ion, 175, 190, 395 symmetry, 182 (CsI)nCs+, 177, 178 Cluster ions, mass-selected, 176 CO, 310 Coating methods, 421 acoustic wave, 421 airbrushing, 421 electrospraying, 421 inkjet, 421 sublimation, 421 Coating, chromium, 445 Coating, Silchrom, 445 Cocaine, 434 Cocaine-d3, 434 Coherent motion, 125 Collision cell, 9 octopole, 208 Collision cross-section, 207, 208, 223 theoretical, 207 Collision energy, 464 normalized, 157–159 Collision frequency, 389 Collision gas, 246 Collision model, hard-sphere, 216 Collision, ion/neutral, 319 Collisional cooling, 278 Collisional dissociation, 392 Collision-induced dissociation, 18, 21, 25, 41, 49, 59–61, 64, 66, 67, 70–72, 90, 92, 96–98, 106, 108, 122, 130, 155–158, 208, 212, 226, 246, 367, 392, 458, 462, 464 beam-type, 23 chemical structure-insensitive, 465 consecutive/competing, scan function for, 373 efficiency, 465 fragmentation efficiency, 66 low energy, 104, 107 multi-level, 464 period, 464, 465 techniques, HASTE CID, 465, 466 techniques, HighQ Pulsed CID, 465, 466 Collisions, thermalizing, 389 COM mode resonance frequency, 300, 301 Combinatorial ligand library bead, 86 Compensation electrode, 346, 347 Compensation voltage, CV, 209, 347

517

Subject Index Complex mixture analysis, 15 Complex, covalently-bound, 71 Concentration gradient, 392 Concentration, maximum allowable, 492 Confinement potential, 335 Conformational dynamics, 170 Conformational family, 219, 223 Conformational fluctuations, 186, 191, 195 peptide, 195, 198 Conformational state, 220 Conformer fluctuations, rate of, 197, 198 Conformer structure, 195 Congener(s), 480, 481, 484 Contact (or patch) potential, 339, 350 Containment lenses, 12 Contaminated extract analysis, 470 Continuous monitoring system, 492 Continuous wave (CW) laser, 188 Controlled substances, monitoring of, 388 Conversion dynode, 452 Cooling rate, 312 Cooling time, 382 Cooling, 377; see also Laser cooling Copper, oxygen-free high conductivity, OFHC, 337, 338 Corona discharge ionization, 8 Corpus callosum, 423, 424 forceps major of, 425 Correction factor Lz, 349, 350 Correlated harmonic excitation fields, CHEF, 131 Correlated sweep excitation, COSE, 131 Correlation method, 344 Coulombic attraction, long-range, 24 Coulombic explosion, 127 Coulombic force, 316 Coulombic interaction, 294, 295, 299, 302, 307, 313–315, 320, 323, 335, 337 Coulombic repulsion, 241, 334 Counter current flow, 388 Creatine phosphokinase, 219 CRL, JAPAN, 359 Cross-linking reagent, cleavable, 104, 105 non-labeled, 103 stable isotope-labeled, 103 Cross-linking strategy, 102 affinity labeled, 103 solution cleavable, 103 stable isotope labeled, 103 Cross-linking, mixed isotope, MIX, 103 Cross-section, absolute, 216, 218 calibration standards of, 215 determination of, 214–216, 219, 221, 223, 227 rotationally-averaged, 208 Cross-sections, comparison of, 218, 219 normalized, 218

Crude oil analysis, 225 Crude vegetable extract, 439, 476, 477 Cryo electron microscopy, 221 Crystal formation, inhomogeneous, 432 Crystal-rich regions, 435, 436 CsI, 177, 178 cluster, 171 C-terminal residue, 19 C-trap, 14 Cu2+, 86 Cumene, 495, 498, 500 Cumene hydroperoxide, 500 Cyclotron frequency, 125, 132, 317 Cyclotron motion, 124, 293, 317 Cylindrical ion trap, CIT, 42, 328 Cysteine residue, biotinylation of, 86 Cytochrome c, 54, 141, 133 Cytochrome C peptides’ solution, 130

D D2, 311 D2O, 12, 36–55 D2S, 38, 43 Daidzein, 155, 156, 162, 163 Daidzein-7-O-glucoside, 155, 156, 162, 163 Damped harmonic oscillator, 303 Damping coefficient, 308 Danish Natural Research Foundation Centre for Quantum Optics, 324 Danish Natural Science Research Council, 324 Database search algorithm, 84 Data-dependent MS/MS method, 139 DC axial potential, 298 DC potential, 12, 341, 346–348 DC turning quadrupole, 419 DC voltage, 317, 339 DDS, see Scan, data-dependent de Broglie wavelength, 177 De novo sequencing, 84 DE50 value, 158, 159, 161–163 Debye–Scherrer rings, 176 Decabromodiphenyl ether, 482 Decafluorotriphenylphosphine, 467–469 Decomposition pathways, consecutive and competing, 373 Degrees of freedom, 157 Deinococcus radiodurans, 129 Deinococcus radiodurans proteome, 140 Dendrimer, 19 Density functional calculation, 182, 248, 251 Density functional theory, 179 Dentate gyrus, 425 Deoxyribose monophosphate nucleotide, 54 Derivatization strategy, 100 DESI, see Ionization, desorption electrospray Desorption ESI, DESI, 224

518 Detection efficiency, 320 Detection limit(s), 447, 491, 495–497, 505 Detector, 389, 394 Deuterating agent, 43, 45 gas-phase acidity and basicity of, 38 Deuteron transfer, 39 DFTPP, see Decafluorotriphenylphosphine DI, 38, 51 Diagnostic ion, 22, 87 Dialysis-related amyloidosis, 220 Dibromochloromethane, 495 Dichloroacetate, DCA, 432 Dichlorobenzene isomers, 498 Dichlorobromomethane, 495 Dichloroethane, 502 Dichloromethane, DCM, 408, 473, 475, 476 Diesel/oil extract, 473–476 Diethylpyrocarbonate, 101 Difenoconazole, 446 Differential isotopic enrichment, 98 Differential stable isotope labeling strategy, 102 Diffraction data, 177, 179, 180, 182, 184, 185 Diffraction pattern, 176, 177, 182–185 analysis, 177 calculated, 171 measured, 171 Digital ion trap, 367, 374, 275 Dimethyl methylphosphonate, 403, 406 Dipolar mode, 368 Direct current (DC) pulse, 370 activation, 369 Discharge source, 4 Disease studies, 425 Dispersed emission spectrum, 255–257 Dispersed fluorescence, 255 Displacement reaction, 411 Dissociation yield, 241 Disulfide bond, selective cleavage, 70, 137 Disulfide linkage, 21, 22 DIT, see Digital ion trap DMDNP, see 2,3-Dimethyl-2,4-dinitropentane DMMP, see Dimethyl methylphosphonate DMNB, see 2,3-Dimethyl-2,3-dinitrobutane DMP, see 2,4-Dimethylpyridine DNA, 60, 246, 424 DNB, see 1,4-Dintitrobenzene Domain, frequency, 459 Domain, time, 459 Dominant conformers, interconversion among, 195 Doppler cooling force, 303, 312, 316 Doppler effect, 301, 312, 332, 339, 348 Doppler laser cooled, 299, 312, 319 Doppler profile, 333, 344 Doppler spectrum, calculated, 333, 334 DPM, see 3-(3-Methoxypropoxy) propanol Dried droplet method, 433

Subject Index Drift cell, 205, 207, 208 IMS, DCIMS, 206, 207 ion mobility–mass spectrometry, DCIM-MS, 207, 208, 215, 216, 218, 223, 224 resolving power, 225 Drift field, electrostatic, 389 Drift gas inlet, 390 methane, 403 nitrogen, 403 Drift length, 397 Drift region, 387, 389, 390, 393 Drift time, 216, 390 Drift tube, 391 cylindrical, 397 DriftScope program, 213 output of, 214 Drosophila melanogaster, 208 Drosophila Toll receptor, 221 Drug, active, 435 Drug, Pro-, 435 Drugs, 419, 433, 435, 436 Duty cycle, 128, 378 fast, 67 rectangular waveform, 374, 375, 378, 385 Dye fluorescence, quenching, 195 Dye–ligand affinity chromatography, 86 Dye–Trp proximity, 191 Dynamic peak range, 455

E e− - trapped ion interaction, 175 e− -beam-cloud overlap, 174 E/N, 391, 407, 408 ECD FT-ICR mass spectrum, 136, 137 ECD mass spectrum, 136 ECD of protein and peptide, 135–138 ECD, principles, 135 ECD, see Electron capture detection Effective collisions, 383 Effusive oven, 299, 342 EI, see Ionization, electron Electric circuit, switchable, 442, 443 Electric field, 205 gradient, 388 strength, 390, 404, 408 dipole, 442 higher-order multipole, 442 quadrupole, 442 Electrical breakdown, 391 Electrodes, coated, 439, 444 hyperbolic angle of, 263 Electrodynamic ion trap, 3, 4, 13, 14, 16, 25 Electromagnetic trap, linear, 357 Electron affinity, 24, 406 Electron association reactions, 411

519

Subject Index Electron attachment rate constant, 407 Electron beam, pulsed, 439, 445 Electron capture, 387, 406 cross-section, 135 detection, 484 dissociation, ECD, 21, 64, 89, 123, 130, 246 dissociative, 400 rate constant, 407, 408 thermal, 387 Electron detachment reactions, 411 Electron detachment, thermal, 387, 406, 409 Electron diffraction, 170, 171 instrument, 172 measurement, 175 pattern, 175 Electron energy, 447 distribution, 407 Electron gun, 172, 297 Electron impact ionization, EI, 36, 342, 503 Electron multiplier, 173, 452 Electron multiplying charge-coupled device, EM-CCD, 257 Electron photodetachment, 241, 254 Electron scattering, inelastic, 176 total, 175 Electron transfer, ET, 12, 20, 24, 60, coupled with PTR, 67 field-induced, 195 photo-induced, 191 plus CID, EtcaD, 64 Electron transfer dissociation, ETD, 6, 8, 15, 17–19, 21, 22, 24, 60, 64, 66, 67, 70, 72, 142 comparison with ETcaD, 65 non-dissociative, ETnoD, 64 multiple, 66 reaction, bio-ion/ion, 21 without dissociation, ET, 24 Electronic action spectroscopy, 252 spectrum, 252 Electronic excitation, 176 Electro-optic modulator, EOM, 302 Electro-optical chopper, EOC, 300, 302 Electrospray ionization, 3, 4, 7–12, 14, 15, 17, 24, 25, 36, 46, 47, 49, 52, 54, 62, 84, 91–93, 103, 154, 160, 207, 210, 215, 221, 253 source, 170, 257 orthogonal, 157 Electrostatic field, 140, 194–196, 392, 403 interaction, 194 lens, 128 e-mail, tranmission of results from unmanned site by, 503 EM-CCD, Newton, Andor Technologies, 257 End lens, 70, 126–128

End-cap electrode(s), 7, 157, 173, 190, 191, 262, 269–273, 276, 303, 337, 341, 345, 347, 350, 367, 368, 372 End-cap electrodes trap, 345, 346 AC voltage applied across, 300, 301, 303, 434 stretched out, 442 Endoproteinase Lys-C digestion, 24 Endrin, 469 Energy-resolved mass spectrometry, ERMS, 155, 157–159, 161, 164 Energy-variation study, 54 Enthalpy, 388, 394, 396 changes, standard, 397, 399 reaction, 398 Entropy, 388, 394, 396 changes, standard, 397, 399 reaction, 398 Enzymic activity, 430 Epicatechin (−), 155, 156, 162–164 Equilibrium, 393 Equilibrium constant, 397 Equilibrium, phase-partitioning, 493 Equine myoglobin, 218 Escherichia coli, 16, 140, 144, 220, 241 ESI, see Electrospray ionization ESI-FT-ICR, 140 ESI-LIT-TOF instrument, 51 ESI-QIT instrument, 51 ETD, see Electron transfer dissociation ETD/CID MS/MS, 64 Ethylbenzene, 492, 495, 497, 498, 500 Ethylbromide, 402, 403 ETnoD, multiple, 66 European Union Directive 98/83, 492 Exact hard-sphere scattering, EHSS, 222 Excimer laser, 252 Excitation probability, 360 non-resonant, 367, 369 resonant, 367, 369, 373, 374 Exciton Corporation, 255 Exogenous compounds, 433 Explosives, detection of, 388, 399 External calibration, 14 Extract(s), contaminated, analysis of, 439 Extractive electrospray ionization, EESI, 224

F Faraday cup, 172, 173, 207 Faraday plate, 390, 398 Fatty acid tail(s), 426, 430 Fatty acyl chains, 423 FC-43, see Perfluorotributylamine Fe3+, 86 FeCO2−, 70

520 FELIX, 246, 248, 249 Fiber optic, 420 Fick’s equations, 493 Field adjusting phase, 375–377 Field asymmetric waveform IMS, FAIMS, 206, 209, 228 Field test(s), 491, 496, 502, 505 Filament assembly, 448 Filtered noise field, 459, 460 Finite-element based program, 345 Finnigan 3D QIT, 67 Corporation, 466 LTQ, 420, 423 LTQ mass spectrometer, 9, 69, 71 Finnigan MAT, 440 First-Doppler effect, 332, 343 First-order Doppler shift, 342, 358 Fixed-charge derivatization, 91 Flavonoid, 154–157, 162–164 Flavonoid glycoside isomers, 49, 50 Fluoranthene, 9, 476 Fluoranthene anion, 68–70 Fluorescence, 294, 300, 334, 341, 348, 353, 418 decay, 190 detection sensitivity, 188 emission, 242, 256, 342, 349, 350, 353 spectrum, 186 excitation spectrum, 255, 256 hole, 266, 270, 271, 274, 275, 278 image from 40Ca+, 300, 307, 308 imaging system, 300 intensity, 187–189, 281, 348 lifetime, 186 measurement, 191, 193 lifetime, temperature dependence, 193, 195, 198 measurement, 191, 334 resonance energy transfer, FRET, 255, 283 spectroscopy, 240, 242, 254, 255 Fluorescent lifetime, 191, 192 Fluorophore, 418 FNF, see Filtered noise field Focusing device, 128 Forbidden optical transition, 332 Forward mass scan, 376, 377 Fourier transform, 174, 191, 460 ion cyclotron resonance, FT-ICR, 9, 15, 19, 42, 44, 45, 51, 121–144, 207, 242, 244–246, 255, 282, 293, 95 analysis, 126 instrument, 51 mass spectrometry, 388, 389, 458 principles of, 122–126 resolving power, 129 sensitivity, 130

Subject Index Fragmentation reaction, selective gas-phase, 107 threshold, 465 site-specific, 93 Franck–Condon factor, 24 Free energy, 388 Free-electron laser, FEL, 244, 246, 247, 251, 282 Free-jet expansion, 396 Frequency metrology, 328, 341, 357–359 Frequency of ion motion, 5 Frequency power spectrum, 269, 270 Frequency reference, 354 Frequency spectrum, 126, 348, 349, 460, 462 Frequency stability, 358 Frequency standard, 358 Frequency synthesizer, programmable, 301, 302, 305 Frictional force, 312, 313 FT-ICR, see Fourier transform ion cyclotron resonance Fundamental secular frequency, ωr,0, 262, 263, 268, 298, 337, 339, 343, 349, 350 Fundamental secular frequency, ωz,0, 262, 263, 268, 271, 298, 337, 339, 343, 349, 350 Fungicide, 446

G Ga3+, 86 Gas chromatography/mass spectrometry, GC/MS, 49, 439, 476, 478, 486, 496 Gas chromatography/tandem mass spectrometry, GC/MS/MS, 439, 440, 442, 454, 455, 457, 470, 486 Gas-phase acidity, 39, 40, 49 basicity, 39, 40 ion, 3 ion chemistry, 41 ions of opposite polarities, 3 reactions, 394 Gaussian peak, near-, 392 Gelatin, 154 General relativity theory, 330 Geometric parameter, η, 298 German National Institute, 345 Glucokinase, 133 Glucose polymer, 227 Glutamine, 129 Glycerol backbone, 423, 425 Glycerophosphocholine lipids, 22 Glycopeptides, 227 Glycoprotein, 134 Glycosylation, 21 Gravitational redshift, 359 Gravity wave, 330

521

Subject Index Greenwich Mean Time, GMT, 329 Grid(s), 389 Ground-positioning system, GPS, 330, 354

H H/D exchange analysis, 53 mass spectra, 48, 49 reaction, 37, 39 historical perspective, 36 deuterating agents, 38 doubly-protonated species, 47 flip-flop mechanism, 40 instrumentation, 42 ion trapping, 42 model compounds, 47 model peptides, 51 motivation for, 41 practical aspects, 40 proposed mechanisms, 38 protein, 51, 53 theory of, 37 H2, 310, 311 Halobacterium salinarum, 142 Haloethanes, 492, 497 Halomethanes, 492, 497 Hard-sphere model, 207, 264, 273 Harmonic potential, one-dimensional, 302 HASTE CID, see Collision-induced dissociation techniques, HASTE CID Hazardous substances, monitoring of, 388 HCT, see High Capacity Trap HD, 310, 311 Head-space, 500 Heart disease, molecular differentiation, 140 Heavy gases, presence of, 372 Heidelberg, 345 Helium, 368, 372, 375, 383, 440, 447 Heme, 430, 432 Hemoglobin, 219 Hemoglobin (Hb) tetramer, 215 Hepatitis B virus capsid protein, 220 Hepatitis C patient, cryoglobulins, 140 Heptabromodiphenylether, 480 Heptachlor epoxide, 469 Hewlett-Packard-Austin, 353 Hexapole ion trap, 340 Hexapole LIT, 14 Hg+, 346, 352–355, 357 High amplitude low frequency, HALF, 16 High amplitude short time excitation, HASTE, 98 High capacity trap, Bruker, 444 High performance liquid chromatography, HPLC, 154, 223, 435 /tandem mass spectrometry, 436 High resolution mass analysis, 14

High sensitivity, 15 High-energy synchrotron radiolysis, 101 Higher-order field, 262–264, 268, 271, 315, 316 Higher-order terms, 314, 315 HighQ Pulsed CID, see Collision-induced dissociation techniques, HighQ Pulsed CID Histidine, 24, 127 Histone PTM state, 70 Hitachi 3DQ mass spectrometer, 42 Hitachi M-8000 ion trap mass spectrometer, 6 Hole, in electrode, 260, 262–266, 269, 270–275, 279, 334 Homochirality, 228 Hot electron capture dissociation, HECD, 137, 140 HPLC, see High performance liquid chromatography HPLC/MS/MS, see High performance liquid chromatography/tandem mass spectrometry Human cerebrospinal fluid, 140 Hb variants, identification of, 228 HeLa cell, 144 nuclear protein, tryptic digest, 21 serum, 85 α-casein, 143 Hybrid FT-ICR instrument, 123, 131, 132, 138, 140 Hybrid instruments, 15 linear ion trap FT-ICR, 138, 139 LIT/FT-ICR instrument, 14 Q-TOF instrument, 213, 214 tandem mass spectrometers, 13 LIT /FT-ICR, 13 Orbitrap, 13 quadrupole/TOF, 13 triple quadrupole/LIT, 9 Hydrate ions, 396 Hydration reactions, 397 Hydrogen atom, labile, 45, 48, 49 non-labile, 49 Hydrogen bonding, intramolecular, 48 Hydrogen/deuterium (H/D) exchange, 36–55, 101, 221, 223 reaction, 36 Hydronium ion, 395 Hydroxyl radical probe, 101 Hyperbolic rods, 338 Hyperboloidal ion trap, 334, 345 Hyperfine transition, 332

I I−, 70 IA, 64, 71 IA coupled with CID, 70

522 Icosahedral capsid, 220 ICR cell, 122–144, 242, 243, 246 Image creation, 417, 421 Image current, 126 Images, chemically-selective, 418 Imaging, 225 mass spectrometry, 417, 426, 430, 435 spatial resolution, 225 system, 319, 320 IM-mass spectrometry, reviews, 209 Immunoaffinity chromatography, 86 IMS, see Imaging mass spectrometry IMS, see Ion mobility spectrometry IMS/MS, see Ion mobility spectrometry/mass spectrometry IMS-Q-TOF mass spectrometer, 208 In+, 355 In vitro chemical derivatization, 94 In vivo metabolic labeling, 94 Incident angle, 420 Informing power, 15 Infrared chromogenic cross-linker, IRCX, 109 Infrared multi-photon dissociation, IRMPD, 41, 109, 123, 133, 243, 244–247, 251–253, 282 In-source collision-induced dissociation, ISCID, 105 Instrument duty cycle, 12 Intermediate electrode, 374 Internal atomic oscillator, 330 Internal calibration, 14 Internal enegy, 369, 465 deposition, 368, 369 Internal standard, 433, 434 International Atomic Time, TAI, 329 Intersystem crossing rate, 198 Intramolecular interaction energy, 197 Intramolecular vibrational redistribution, IVR, 245, 249–251, 253 Ion activation, 5, 370, 439, 461 data-dependent, 64 infrared photon, 64 Ion attachment, IA, 60 Ion charge control (ICC) value, 281, 282 Ion clocks, current research, 352 Ion cloud, 174, 175, 188, 242, 243, 255, 258, 260, 264, 279, 280, 335, 337 overlap, 10, 264, 280, 348 size estimation, 278, 345 imaging, 342 increased density, 189 linear, 334 manipulation, 170, 342 spatial distribution, 278, 335, 348, 350, 358 trapped, 173, 349, 351

Subject Index Ion cyclotron motion, 123 Ion cyclotron resonance cell, 124, 242 mass spectrometer, 37 Ion detection, 11 efficiency, summary, 274 Ion ejection, 272 efficiency, summary, 274 Ion ensemble, spatial distribution of, 279 Ion fluorescence, 170, 307, 309, 310 Ion fragmentation, 7, 11, 212 Ion genealogy, 5 Ion guide, 13 RF-only, 208 Ion injection, 7, 10, 11 efficiency, 11 Ion internal energy, 61, 158 Ion isolation, 5, 10, 439, 455 Ion kinetic energy, 12, 369, 372, 446, 447 Ion manipulation, 72 Ion micro-motion, 345, 353, 359 Ion mobility spectra, 391 Type 1, 393, 395 Type 2, 393, 400 Type 3, 394, 403 Ion mobility spectrometer, hand-held, 396 Ion mobility spectrometry, IMS, 205, 387, 388, 417, 419 Ion mobility spectrometry/mass spectrometry, 394, 397, 399, 402, 403, 411 Ion mobility, IM, 205, 207 Ion mobility-mass spectrometry, 205–230 traveling wave, 205–230 applications, 205–230 Ion motion detection, 302 Ion motion frequency(ies), 348 Ion motion in QIT, dynamics of, 261 Ion motion, theoretical treatment, 262 Ion number density, 12, 16 Ion optical clock, 355 Ion parking, 16, 17, 25, 66 Ion photo-excitation, 242 Ion processing, multi-stage, 63 Ion production region, 310 Ion reaction vessel, 60 Ion selection, 370 Ion shutter, 389, 390, 392 Ion source, external, 446 moveable, 397 multiple, 62 Ion spin exchange, 328 Ion splat events, axial distributions of, 273 Ion storage time, variation of, 36 Ion swarm, 390 Ion temperature, 316, 319, 343, 354 Ion tomography study, 278

Subject Index Ion trajectory calculation, 263–266 Ion trajectory simulation, 189 Ion trajectory sImulation software package, ITSIM, 264, 276 Ion trajectory, Fourier analysis of, 263, 266, 268, 271 stable, 261, 262, 268 unstable, 262 Ion transmission mode, 12 Ion transmission time, 12 Ion transmission, efficiency, 7 Ion trap detector, 440 Ion trap dimensions, 5 Ion trap geometry(ies), 328 Ion trap housing, 258 Ion trap imperfection, 315 Ion trap loading, 317, 319, 321 Ion trap mass spectrometer, 60, 170, 187, 190, 239–284, 492 Ion trap parameters, choice of, 323 Ion trap technology, 170 Ion trap, 2D LC/MS, 447 Ion trap, micro, 295 Ion trap, miniature, design, 343 Ion trap, non-linear, 439 Ion trap, Paul-Straubel type, 347, 349 Ion trap, quadrupole, 455 Ion trap, quasi-miniature, 339 Ion trap, segmented, 338 Ion trapped simultaneously, 299, 307, 323 Ion trapping, 328 charge-sign independent, 63, 64 efficiency, 11, 349, 446 parameter, 261, 297, 320 technique, 328 Ion traps, millimeter-scale, 345, 352, 357 multi-pole, 335, 336, 339 Ion, doubly-charged, 223 forced motion of, 300-303 metal cluster, 169, 170, 173 multiply-charged, 241 sequence-informative, 70 Ion/ion chemical reaction, 60 Ion/ion chemistry, 7, 12, 15, 61, 72 Ion/ion ETD reaction, 9, 14 Ion/ion interaction, 348 Ion/ion proton transfer reactions, 15 Ion/ion reaction, 3, 4, 6, 8–11, 15, 17–20, 25, 61–63, 66, 68 cation-switching, 20 efficiency, 5 kinetics, charge-squared dependence of, 16 sequential, 14 tools, 4 vessel, 14, 64 Ion/molecule chemistry, 389

523 Ion/molecule interaction potential, 396 Ion/molecule processes, 392 Ion/molecule reaction, 62, 207, 387, 393, 395, 396, 445–467 association, 411 time, 446 Ion/molecule research, 440 Ion/neutral association, 392 Ionization efficiency, 12 Ionization energy, 447 Ionization time, 372 duration of, 441, 466 fixed, 466 Ionization, ambient, 225 Ionization, chemical, 36–40, 63, 69, 439, 447, 448, 453, 466 external, 450 hybrid, 448, 451, 454, 486 internal, 451 liquid, 439, 448–450, 481, 486 negative, 451 positive, 451 pulsed positive ion negative ion, see PPINICI reagent, 448, 481 gas pressure, 448 ions, 449 selective-ejection, 448, 449 self-ejection, 448 source, 70, 71 /tandem mass spectrometry, 483, 484 Ionization, desorption electrospray, 418 Ionization, electron, 299, 310, 444, 447, 453, 466 Ionization, internal, 444, 445 Ionization, self-chemical, 445 Ion-manipulation methodology, 60, 64 Ion–molecule complex, 37, 40, 42, 44 Ions, collisional cooling of, 262 Ions, laser-cooled, 345 Ions, mobility separation of, 212 Ions, negative, 388, 393, 406, 411 Ions, positive, 388, 411 Ions, precursor, 456, 457 Ions, simultaneous trapping of both polarities, 9 Ions, spectroscopy of, 239–284 Ion-trap dimension, r 0, 298 z0, 298 Ion-trap electrodes, 318 Ion-trap frequency, 320, 321, 323 relative shift, 318 Ion-trap-oscillator ensemble, 328 Ion-trapping device, 227 gas-phase, 73 IP-MALDI, see Matrix-assisted laser desorption, intermediate pressure

524 IRMPD action spectrum, 247–249 IRMPD FT-ICR mass spectrum, 134 IRMPD MS/MS, 140 IRMPD of protein and peptide, 133–135 IRMPD, principles, 133 Iron-containing ions, 6 ISCID mass spectral scan, 106 Isoaspartic acid residue, 22 Isobaric interferences, 429, 432 Isobaric ion identification, 417, 427 Isobaric ions, 428, 436 Isobaric separation, 429 Isobaric species, 427 Isobars, 427, 428 Isolation resolution, 457 Isolation window, 428, 433, 434 Isolation, low mass, 456 Isolation, notch, 457, 460 Isolation, two-step, 456, 457 Isoleucine, 137, 140 Isomer differentiation, 47, 49 Isomer diffraction pattern, calculated, 183 Isomer space filling structure, 181 Isophthalic acid, 48 Isotope effect, 311 Isotope-coded affinity tag, ICAT, 94, 96, 97 Isotopic cluster ions, 478 Isotopic patterns, 503 Isotopic peaks, 441 Isotopomer peak, 458 Isotopomers, 378 Italy, laws, 492 ITD, Finnigan Corporation, 370 ITD, see Ion trap detector ITD-700, 466 ITD-800, 466 ITMS, see Ion trap mass spectrometry ITQ, see Thermo Scientific ITQ, 451 iTRAQ approach, 97, 98 iTRAQ reporter ion, 99 iTRAQ-labeled peptide, 100 ITS-40, 440, 467 IVR killer mode, 251

J Jet Propulsion Laboratory, JPL, 329, 337, 339, 340, 352, 353, 355 JPL geodetic receiver, 354 Jumping, 377

K Kinetic constants, 394 Kinetic data, 387, 391, 394 Kinetic energy, 382, 383, 391, 431, 464

Subject Index Kinetic shift, 243, 245, 253 KinFit, 45, 47 Knudsen oven, 178

L Laboratoire national de métrologie et d’essais, Système de références temps espace, LNE-SYRTE, 331, 353 Lamb-Dicke parameter, 333, 339 regime, 333, 335 Laser beam, 242, 295, 297, 299, 323, 334, 347, 419 Laser capture microdissociation, 435 Laser cooling, 294, 301–304, 311–313, 318–321, 328, 332, 333, 335, 339, 341, 342, 356, 357 process, 358 Laser desorption/chemical ionization, 419 Laser diode, 328 Laser dye, 252 Laser hole, 266, 270, 271, 274, 275, 278, 280, 339 Laser modulation, 303, 305 Laser power, 281, 282, 422, 423 Laser spot size, 421 Laser tuning, 360 Laser, CO2, 243-246 Laser, fixed-wavelength, 240, 242, 243 Laser, Nd:YAG, 243, 252, 257 Laser, nitrogen, 243 Laser, titanium:sapphire, 252, 257, 281, 357 Laser, tunable IR, 244, 245, 247, 256 Laser, vacuum UV fluorine, 244 Laser-cooled mercury ions, string of, 339 Laser-induced fluorescence, LIF, 255, 257 Laser-induced reaction spectroscopy, 250 LC CID MS/MS analysis, 141 LC/MS, see Liquid chromatography/mass spectrometry LC/MS/MS, see liquid chromatography/tandem mass spectrometry LC/MSn, see Liquid chromatography/tandem mass spectrometry LC-ESI-MS, 156 LCM, see Laser capture microdissociation LC-MS/MS analysis, 85, 86, 96, 100, 140 LCQ, 444 Advantage ion trap mass spectrometer, 157 LD/CI, see Laser desorption/chemical ionization Leak valve method, 44 Lectin affinity chromatography, 86 Leucine, 137, 140 Leucine encephalin, protonated molecule of, 379–381

Subject Index Lifetime measurement, 193, 194 time-resolved, 189 Linear extended ion trap, LITE, 339, 354 Linear ion trap standard, LITS 1–4, 354 Linear ion trap standard, LITS project, 352 Linear ion trap, LIT, 9–11, 15, 24, 25, 42, 62, 63, 69, 86, 92, 98–100, 255, 294–297, 300–302, 310, 311, 313, 334, 337, 359, 424, 425, 442 chamber, 52 quadrupole array, 9 sketch of, 296 Linear polarizer, 302 Linear trap ensemble, 340 Linear two-dimensional (2D) quadrupole ion trap, 9, 337, 339 Linear two-ion system, 293, 294, 300, 303, 305, 307, 308, 315 Linearity, 491, 498, 505 Lipids, 419, 422, 424 Liquid chromatography, LC, 84, 208 /mass spectrometry, LC-MS, 49, 422, 442 /mobility separation, 228 -tandem mass spectrometry, LC-MS/MS, 64, 422, 442 Liquid nitrogen, 175 LIT, see Linear ion trap LIT-CID MS/MS, 141, 142 LIT-FT-ICR instrument, 140, 143 LIT-TOF system, 53 LMCO, see Low-mass cut-off Local atomic oscillator, 330 LOD, see Detection limits Logic atomic clock, 356 Low-critical energy process, 371 Low-mass cut-off, LMCO, 5, 64, 101, 104, 241, 372, 439, 465 LTQ, 420, 431, 432, 442 Orbitrap XL, 14 Luteolin, 155, 156, 162, 163 Luteolin-4′-O-glucoside, 50, 155, 156 Luteolin-7-O-glucoside, 50, 155, 156 Lysine, 24, 127, 129 Lysophosphatidylcholine, 430 Lysozyme, 54, 141

M Machinable macor, 346 Macromolecule ions, 19 metal-containing, 21 Macromolecule mixture analysis, 15 Macro-motion, 348, 352, 353 Magnesium, 319 Magnetic field, Earth, 317 residual, 317 Magnetron motion, 124

525 MALDI, 15, 42, 46, 84, 93, 126, 139, 156, 207, 210, 215, 225, 241, 243, 417–419, 422, 424, 429, 430, 433, 435, 436 MALDI-FT-ICR, 140 MALDI-QIT instrument, 51 Malondialdehyde, 88 Mapping, 377 Marseille, 329, 347, 359 Mass accuracy, 14, 15, 468 Mass analysis, 11, 13 data-dependent, 65 high-sensitivity, 67 Mass analyzer, 14 Mass discrimination, 392 Mass filter, 13 Mass isolation window, 10 Th, 157, 159 Mass range, 419 Mass ratio μ, 296, 303, 314, 322 Mass resolution, 310, 324, 468 higher, 439, 442 Mass spectrometric imaging, full-scan, 417, 429 tandem, 328, 417, 429 Mass spectrometry region, 310 Mass spectrometry, identifying ions by, 392 Mass spectrometry/mass spectrometry, see Tandem mass spectrometry Mass spectrum, ‘quadrupole like’, 468 Mass spectrum, simulated, 274–277 Mass spectrum, Synapt, 214, 219 Mass-resolving power, 14, 15 Mass-selected ions, optical spectroscopy of, 240 Mass-selective axial ejection, MSAE, 9, 11 instability scan, 371, 375 Mass-selective external ion accumulation, 138 Mass-selective instability, 259, 264, 272, 273, 276, 440, 441, 456 Mathieu equation, 348, 374 Mathieu parameters, 374 Matlab v. 7.0, The Mathworks, Inc., 228, 266 Matrix cluster ions, 429 Matrix effect(s), 12, 491, 499 Matrix ions, 424 Matrix solution, 421 Matrix-assisted laser desorption, atmospheric pressure, AP-MALDI, 419 intermediate pressure, 417, 430 intermediate vacuum, 420, 423, 431, 432 ionization, see MALDI Max Planck Institute, 359 m-Difluorobenzene, 37 Medial genticulate body, 425 Melittin, 67, 68 Membrane inlet mass spectrometry, MIMS, 491, 493, 494, 500–502, 505 Mercury, 327, 332, 334, 352, 356 Mercury ion, 329, 332, 334, 337, 339, 352 Messenger spectroscopy, 250

526 Metabolites, 418, 419, 422, 424, 435, 436 Metal cluster aggregation sources, 170–172 collisional relaxation, 175 ion source, 174, 175 Metal transfer, 20 Metal-ion affinity chromatography, IMAC, 86 Metal-ion insertion, 25 Metal-ion transfer, 15, 19, 20 gas phase, 20 Metal–oxide affinity chromatography, MOAC, 86 Metastable state, 342 Methane, 403 Methanococcus jannaschii, 144 Methanol, 481 Methionine residue, 91 Method detection limit, MDL, 485, 486 Methyl bromide, 401–403, 411 Mg+, 295, 299, 311 MgD+, 305, 310, 311 MgH+, 305, 310, 311, 324 Microcrystals, 435 Micro-extraction, 484 Micromotion, 316, 344 amplitude, 334, 335 minimization of, 344 Microwave frequency domain, 329, 333, 352 Microwave frequency standard, 334 Microwave interrogation, 339 Microwave-assisted D-cleavages, 24 Military preparedness, 411 Minimum energy conformation, 248, 251 Mirror image, 256 Mobile proton condition, 87, 90 Mobilities, differences in, 390 Mobilitiy measurement(s), 387, 389 Mobility cell, 227 Mobility coefficient, 396 Mobility data, 213, 226 Mobility gas, 218 Mobility separation, 224, 228 Mobility spectrum, 387 Mobilogram, 213, 214 Model proteins, top-down study, 18 Modes, electronic, 388 rotational, 388 translational, 388 vibrational, 388 Modification, S-type, 108 unique, 107 Modulation frequency, 305 Modulation voltage, 300, 301, 307 Molar Gibbs energy, ΔG, 38 Molecular beam, 295 Molecular dynamics, 161, 191, 219, 251 simulation, 191, 195, 197, 207 Molecular ion cluster, 379

Subject Index Molecular ion, photodissociation, 311, 323 Molecular ions, 310, 323 Molecular mechanics force field, 251 Molecular scattering curve, 178, 179 Molecular scattering data, 180 Molecular scattering intensity, 177, 178, 181, 182 Molecular weight distribution, 227 Molybdenum, 337, 345, 347 Monitoring, 388 prolonged, 491 Monoclonal antibodies, glycosylation of, 226 Monoisotopic mass, 129 Monoisotopomer, 378, 379 MS/MS, see Tandem mass spectrometry MSn, see Tandem mass spectrometry, multiple stages of Multiphoton dissociation, 250, 251 Multiple collisions, 369 Multiple decomposition channels, 369 Multiple photon process, 250 Multiple resonant frequencies, 480 Multiple stages of mass selectivity, MSn, 60 Multiply-charged anions, 7 Multiply-charged cations, 6 Multiply-charged ion, 3, 4, 18, 19, 61, 127 Multiply-charged precursor ions, 17 Multiply-charged reagent ions, 19 Multiply-protonated polypeptides, 6 Multipole storage-assisted dissociation, MSAD, 131 Multipoles, higher-order, 443 Multi-sector mass spectrometers, 368 Mutual ion storage, 6, 10 Mutual ion storage mode, 9, 13, 14 Mycobacterium tuberculosis, 144 Myoglobin, 133, 215, 218

N NADH dehydrogenase 1 beta sub-complex 3, 99 n-Alkyl bromide, 400–402 Nanoelectrospray ionization (nESI) source, 187, 190 Nano-liquid chromatography, 130 Nano-spray static tip, 62 Naringenin, 155, 156, 160, 162, 163 Naringenin-7-O-neohesperidoside, 155, 156, 160, 162, 163 NASA Deep Space network, 354 National Burean of Standards, NBS, 329 National Institute of Standards and Technology, NIST, 251, 329, 337, 338, 346, 353, 354, 356, 357, 396, 398 National Institutes of Health, 55 National Physical Laboratory, NPL, 329, 346, 359 National Research Council, NRC, Canada, 359

527

Subject Index Natural Sciences and Engineering Research Council, Canada, 284 N-Benzyliminodiacetoylhydroxysuccinimid, BID, 104 NCI, see Ionization, chemical, negative ND3, 37, 38, 40, 43, 51, 54 NDBA, 483 NDEA, 483 NDMA, 483 NDPA, 483 Negative chemical ionization source, 15 Negative ETD reagent ions, 14 Negative ions, 15 Neohesperidin, deprotonated, 47 Nephelometry, 154 Neurotensin, cross-linked, pELYENKPRRPYIL, 107, 108 Neutral loss, NL, 429 Newton’s equations of motion, 264 NH3, 329 Nickel acetate, 20 NIST Chemistry WebBook, 38 Nitrobenzene, 6 Nitro-compounds, 472 Nitrogen, 403, 406 Nitrophenols, 472 Nitrosamines, 483 NMEA, 483 Nobel Prize for Chemistry (2002), 127 Nobel Prize for Physics (1989), 328 Nomenclature, backbone product ions, 131 Non-exchanged isotopic contribution, 45 Non-linear field component, 260, 261, 263 Non-linear ion trap, see Ion trap, non-linear Non-linear resonance, 263, 268, 348, 350 Non-mobile proton condition, 87 Non-zwitterion, 247–249 Normalized collision energy, NCE, 463 Notch window, 460 Nozzle-skimmer dissociation, 131 NPIP, 483 NPYR, 483 N-terminal derivatization, 88 Nuclear magnetic resonance, NMR, 221 spectrometry, 154, 228 Nucleic acid, 54 mixture analysis, 16 Nucleoside, 54 Numerical simulation, 298

O O2, 319 Oak Ridge National Laboratory, 492 Octopole ion guide, 9, 15 o-Difluorobenzene, 37 Office of Water, 468

Off-resonance excitation, 41, 132 Oleic acid, 426 Oligodeoxynucleotide anions, 20 multiply-charged, 20 Oligonucleotide, 15, 54, 223 One-liter trap, 340, 341 Oppositely-charged ion populations, 4 Optical cavity-laser, 355 Optical frequency comb technique, 356, 357 Optical frequency domain, 333, 341 Optical frequency ion clock, 358 Optical frequency standards, clocks for, 341 Optical parametric oscillator, OPO, 247, 252 Optical spectrum, 240 Orbitrap, 12 Orbitrap mass spectrometer, 100 Organohalogen compounds, 497, 503, 505 Organomercurial agarose bead, 86 Organophosphate chemical warfare simulant, 228 Organophosphorus compounds, 403 Orthogonal reflectron TOF mass analyzer, 13 Oscillation frequency, 299, 303, 305, 308, 309, 314–316, 318, 319 Oversampling, 422

P P&T/GC/MS, see Purge-and-trap/gas chromatography/mass spectrometry Paclitaxel, 419 Pair correlation function, Fourier transform of, 171 Parallel ion parking, 16, 17, 25 Partial proton transfer reactions, 17 Paul trap, 5, 341, 349, 351; see also Quadrupole ion trap ion trap, 240, 242, 245, 246, 255, 257, 296, 346 PBDE-100, see 2,2′,4,4′, 6-Pentabromodiphenylether PBDEs, see Polybrominated diphenyl ethers PC, see Phosphatidylcholine PCBs, see Polychlorinated biphenyls PCI, see Ionization, chemical, positive PD, see Photodissociation PE, see Phosphatidylethanolamine Peak tailing, chromatographic, 445 Penning trap, 245, 296 Pentachlorophenol, 472 Pentapeptide, protonated, 51 Peptide backbone bond, multiple breakage, 67 Peptide backbone, 19 Peptide cation, multiply-charged, 71 Peptide identification, 96

528 Peptide ions, 372, 382 differentially-labeled, 97 multiply-protonated, 24 Peptide mass fingerprinting, 139, 140 Peptide mixture, simple, 19 labeled, 97 Peptide sequencing, 140 Peptide subset, chemical derivatization of, 86 Peptide, amino acid sequence, 84 analysis, 121 cross-linked, 102, 106 cysteine-containing, 86, 92, 101 dead-end modified, Type 0, 102 doubly-protonated, 71 highly-charged precursor, 67 histidine-containing, 86 identification of cross-linked, 105 intermolecular cross-linked, Type 2, 102–105, 107 intramolecular backbone bonds, 70 intramolecular cross-linked, Type 1, 102, 104 methionine-containing, 91 methionine sulfoxide-containing, 87 N-acetylgalactosamine-containing, 87 phosphorylated, 86, 223 photodissociation, 109 Peptide–polyphenol, 153–164 gas-phase affinity scale, 155, 161, 164 supramolecular assembly, 153–164 tannin, 153 Peptides, 419, 422, 424 multiply-deprotonated, 21 three-dimensional structures of, 207 Perfluoro-1,3-dimethyl-cyclohexane, PDCH, 6, 67 Perfluorotributylamine, PFTBA, 452, 454, 457 Periaueductual gray, 425 Period, injection, 454 isolation, 454 Permanent magnet, 126 Permittivity of vacuum, 302, 337 Pervaporation, 493 Pe-scan, 444 Pesticide(s), 477 Phase method, 320, 321, 323 Phase shift, 272 Phase-detection method, 305, 309 Phenanthrene, 452, 453, 455 Phenylboronic acid, 101 Phenylisothiocyanate, 89 Phosphatidylcholine, 423, 425–428, 431 Phosphatidylethanolamine, 428–430 Phosphatidylinositols, PI, 424 Phosphatidylserine, 428–430 Phosphocholine, 425 head group, 431

Subject Index Phospholipid ion, 429 Phospholipid(s), 422, 425, 426, 432, 433 Phosphopeptide ion, deprotonated, 19 Phosphopeptide ions, 19 CID, 22 doubly-protonated, 19 ETD, 22 methyl-esterified, 21 Phosphoric acid, losses of, 21, 142, 143 Phosphorus hexafluoride, 70 Phosphorylation, 21, 137 Photodissociation, PD, 240, 241, 252, 257, 282, 283, 369 Photoelectron spectroscopy, 182 Photo-induced dissociation, PID, 240 Photoionization beam, UV, 318, 319, 342 Photoionization, resonance-enhanced, 299 Photon detection, 319 PHPMS, see Pulsed high pressure mass spectrometry Phthalates, 472, 473 Phthalic acid, 48 isomers, 48 Physikalisch-Technische Bundesanstalt, PTB, 345, 359, 360 Planck’s constant, 341 Plasma chromatography, 206, 388 Plasma ECD, 138 mass spectrum, 138 Polarized compounds, 444 Polarized light microscopy, 435 Pole number, 336 Polybrominated diphenyl ethers, 478, 480, 481 Polychlorinated biphenyls, 439, 483–485 Polycyclic aromatic hydrocarbons, 392 Polyethylene glycol, PEG, 227 Polynuclear aromatic compounds, PNAs, 452, 454, 473 Polypeptide, 15 cation, multiply-charged, 21 ion, 9, 20 multiply-protonated, 21 Polyphenol, structure of, 153, 155 Polyproline lifetime measurements, 191 Polyproline peptide, 186, 190, 191 dye-derivatized, 189, 191 Polyvinylpolypyrrolidone, PVPP, 154 Porapak, 498 Porcine elastase, 18 Position specific mass spectrum, 421 Positive ion mode, 426 Post-ion/ion reaction (PTR) MS3 spectrum, 68 Post-mortem human brain tissue, 434 Post-translational modification, see PTM Potabilization, 497, 502 Potential well depth, 195, 299, 319, 335, 336, 339, 342, 345, 347, 350

Subject Index PPINICI, 448, 451 PQD-MS/MS, 98–100 Precision mass measurement, 309, 315 Precursor ion, 367, 368, 372, 373, 419, 427, 464, 465, 472 charge-state manipulation, 15 doubly-charged, 383 isolation, 61, 131 Precursor ions, higher-charged, 67 Pre-exponential factor, 405, 406, 411 Pre-ion/ion reaction (PTR) MS/MS spectrum, 68 Pre-scan, 422 Pressure, effect of increasing, 430 Prion diseases, 220 Prion protein, 220 Product ion, 367, 368, 383, 385 diagnostic, 91 manipulation, 18 mass spectra at selected working points, 384 in silicio, 18 mass spectra, simplification, 15, 17 mass spectrum, 10, 18, 21, 23, 66, 69, 84, 90, 91, 96, 108, 227, 372 multiply-charged, 69 selected ejection of, 373 transition, 427 a-type, 88, 89, 137 b-type, 67, 87–89, 98, 100, 109, 132, 133, 137 c-type, 69, 136, 137 y-type, 67, 87–89, 98, 100, 109, 132, 133, 137 z-type, 69, 136, 137 Product ions, 428 singly-charged, 383 Projet d’Horloge Atomique par Refroidissement d’Atomes en Orbite, PHARAO, 332 Proline residues, 16 Proline rich protein, PRP, 154, 155 primary structures, 156 synthetic, 154 synthetic B714, 155–157, 159, 161–164 IB8c, 155, 156, 163 IB934, 155, 156, 160, 162, 163 Protein A, 134 Protein analysis, 16 Protein and peptide depletion, 85 separation, 85 Protein backbone cleavage, 71 Protein conformation, 224 Protein database search, 21 Protein digestion, enzymatic, 59 Protein expression, 93 Protein folding, 101, 209 dynamics, 101 Protein identification, 14, 85

529 Protein interaction reporter, PIR, 105 Protein ions, fragmentation of, 16 Protein mis-folding diseases, 220 Protein mixture, 17 analysis of, 15 Protein quantitation, 93, 95 analysis, label-free, 94 stable isotope label, 94 Protein sequence analysis, 61 Protein sequence characterization, 72 Protein Sprouty2, 143 Protein stability information, 220 Protein structural characterization, 83 Protein structure, 101 Synapt, 219 Protein topology, low-resolution structure of, 101 Protein, analysis, 121 conformations of, 53 differential quantitative analysis, 93 highly-charged precursor, 67 multiply-protonated, 52 multiply-deprotonated, 52 Protein–polyphenols, interaction of, 154 Protein-protein interaction, 101, 102, 105, 106 Proteins, 422, 424 lubricating salivary, 154, 164 Proteome, human plasma, 208 Proteome, mouse brain, 86 Proteome, urinary, 208 Proteomic analysis, amniotic fluid, 140 Proteomics approach, LC-ESI-MS/MS, 229 Proteomics research, MS-based, 84, 223 Proteomics, application of FT-ICR, 139 Proteomics, bottom-up approach, 70, 84, 85, 101, 123, 139 Proteomics, major goals, 84 Proteomics, shotgun approach, 84, 140 Proteomics, top-down, 18, 60, 123, 139, 143 Proton affinity, 392, 449 Proton hydrate, 395 Proton mobility, 106 Proton transfer, 11, 12, 15, 24, 39, 64, 105, 395 multiple, 12, 19 reaction, PTR, 6, 16–18, 60, 449 sequential, 19 Proton-bound dimer(s), 403, 404, 406 Proxy marker, 60 PS, see Phosphatidylserine Pseudo-first order, 392, 401 Pseudo-potential trapping well, 5, 6, 339 Pseudopotential well, cross-section, 335, 336 PTM, 14, 59, 64, 72, 136, 142 PTM information, 21, 26 PTM motif, 70 PTR, 61, 66, 67, 70 Pulse width, 392

530 Pulsed axial activation, 369 Pulsed double ionization sources, 12 Pulsed dual ion source, 13, 14 Pulsed dual polarity ionization source, 12 Pulsed high pressure mass spectrometry, 389, 396, 398, 402, 406, 409 Pulsed laser, 187, 189 Pulsed Q collision-induced dissociation, PQD, 98, 99 Pulsed triple ionization source, 12 Pulsed-valve method, 44 Purge-and-trap/gas chromatography/mass spectrometry, 491, 492, 494, 496–498, 500–502, 505 Pyridine–pyridine, 397 Pyridine–water, 397

Q qcut-off, 371 QIT, see Quadrupole ion trap QIT Esquire 3000+, Bruker Daltonics, 257, 259, 261, 263, 264, 266, 270, 272, 275, 277, 278, 281, 282 QQQ, see Triple-stage quadrupole qr, 298, 368 QSTAR XL, Applied Biosystems/MDS Sciex, 13 Q-TOF hybrid instrument, 208, 223, 224 QTRAP, 64, 66 Q-Trap 2000, Applied Biosystems/MDS Sciex, 9 qu, 261 Quadratic phase relation, 459 Quadrupole array, 11, 12 Quadrupole bender, 171, 173 Quadrupole field, quasi-pure, 345 Quadrupole ion trap, 36, 42, 45, 46, 54, 61–64, 67, 70, 87, 88, 90, 96, 97, 101, 107, 190, 207, 208, 211, 240, 244, 253, 255, 258, 260, 262, 328, 339, 367, 369–371 electrodes, cross-section of, 265 instrument, 51, 104, 140 home-built, 186–188 hyperboloidal geometry of, 328 mass spectrometer, 60, 84, 155, 173 modification for spectroscopy, 257 modified hyperboloidal angle, 264, 268, 281 non-ideal, 261 Quadrupole mass filter, 215, 293, 295, 297, 334, 339, 467 Quadrupole mass spectrometer, 398 Quadrupole time-of-flight, QTOF, 97 Quadrupole-FT-ICR, 138 Quantification, 417, 432 Quantum entanglement, 356 Quantum information, 328

Subject Index Quantum jump, 342, 343 number, 360 Quartz crystal, beating, 329, 352 Quasi-stable, 372 QuEcHERS, 476 Quenching measurement, 191, 193 Quenching rate, 191, 194–196 model, 193–195, 197 temperature dependence of, 192–194 Quercetin, 155, 156, 162, 163 Quercetin-3-O-rhamnoside, 156 Quercetin-3-O-rutinoside, 155, 156, 162 Quercitrin, 50 QUISTOR, 328 qz, 173, 174, 191, 259, 261, 268–272, 278, 280–282, 350, 368 qz-axis, 370 qz-value, 446, 465

R Radar, development of, 329 Radial ion ejection, 11 Radial trap frequency, 300 Radiation pressure force, 301 Radiative lifetimes, 169 Radio frequency (RF) cavity, 332 ion trap, 169, 171, 238, 346 Radiofrequency domain, 332 Ramsey fringe, 332 Raster-step size, 422 Rat brain, 423, 424 tissue section, 425 Rate constant, 393, 394 ion/molecule reaction, 398 Rate equation analysis, 192 Rats, control, 432 Rayleigh length, 188 Reactant ion peak, RIP, 395 Reaction kinetics, 36 Reaction rate constant, measurement of, 387, 403, 404, 411 Reaction time, 392, 401 window, 16 Reaction vessel, 12 Rectangular wave voltage, periodic, 374 Rectilinear ion trap, RIT, 42, 44 Reduced mobility, 397, 406 coefficient, 391 K0, 207 Reference measurement, 321 Relative mass resolution, 293, 295 Remotely-controlled instruments, 494 Repeatability, 505 Reporter group ion, 98 Reproducibility, 491, 498 Residence time, 389

Subject Index Residual magnetic field, 317 Resolution, mass, 441, 467 Resonance ejection, 6, 132 scan, 440, 467 Resonance excitation, 157, 264, 294 /ejection, 382 Resonance frequency, 294, 313 ω+, 304, 305, 307, 317, 322 ω−, 304, 317, 322 Restriction of Hazardous Substances, RoHS, 478, 481, 482 Reversed-phase chromatography, 96, 101 Reversed-phase liquid chromatography, 156, 192 RF barrier, 9 RF circuit, 259, 260 RF drive voltage amplitude, 334, 335 RF electric field, 334 RF frequency, 298, 307, 314, 322, 341–343, 345–347 RF gain curve, 259 RF ion trap, 188, 294 RF linear trap, 332 RF modulation, 462 RF photon correlation, 342 RF potential, 175, 258, 259, 301, 316, 338, 345, 346, 350 RF power supply, 355 RF ramping, 191 RF unbalance, 9 Rhem–Weller observation, 197 Rhenate, ReO3− and attachment mechanism, 71, 72 Rhodamine 101, 272, 274, 275, 277 Rhodamine 590, 255, 256, 281 Rhodamine 640, 188, 189 Rhodamine 6G, 255 Ring electrode, 7, 191, 258–265, 270, 271, 275, 339, 345, 348, 350, 371, 374 stacked, 208 Ring trap, 347 Ring-down time, 241 Robert A. Welch Foundation, 55 Round rods, 338

S Saccharomyces cerevisiae, 96, 142 Safe Water Drinking Act, SWDA, 468 Sample gas inlet, 390 Sample preparation, 421 Saturn 2000 3D, 449, 467 Saturn 4D, 440 Saturn, Varian, 370 Saturn-I, 440, 467 Saturn-II, 467 Saturn-III, 467

531 Saturn-IV, 467 Scan function, 371, 372, 374 chemical ionization, 449 triple resonance, 442, 467 Scan speed, 443 higher, 439, 442 Scan table, 374, 382 Scan, data-dependent, 464 stepped normalized, 464 Scattering rate, 320 Sciatic nerve, 432 SCSI-MS instrument, sketch of, 294 Second, time unit, 329 Secondary ion mass spectrometry, SIMS, 418 Second-Doppler effect, 332, 334, 339, 354, 359 Secular frequency(ies), 16, 317, 368, 457, 462, 463 Secular frequency, see Fundamental secular frequency summary of calculated values, 267 SELECT, 91, 92, 100 Selected reaction monitoring, SRM, 427 Selective ion monitoring, SIM, 469 Selective ion storage, SIS, 467 Self-CI, see Ionization, self-chemical Sequence coverage, complete, 21 Sequence information, 21 complementary, 21 Serine octomer, conformational structure of, 228 Serum albumin, 134 Servo-loop, 343, 353 scheme, 330 Sewage treatment plant, 503, 505 Shewanella oneidensis, 144 Shuttle trap, 339 Sickle-cell anemia, 222 Side-chain losses, 24 Sigma Aldrich Corporation, 255 Signal-to-noise ratio, S/N, 383, 447 Silver nitrate, 20 SIMION model parameters, 265 SIMION v. 8, Scientific Instrument Services Inc, 261, 263–268, 273, 278, 345 Simulation trajectories and histograms, 195 Dye–Arg+, 195, 196 Dye–Trp, 195, 196 Trp–Arg+, 195, 196 Single ion oscillation frequency, 302 Single ion preparation, 341 Single ion, sympathetically-cooled, 291, 299, 300 Single trapped ion, 170, 333, 342, 345–347, 355, 357, 360 laser spectroscopy of, 170, 342, 345, 346 Single-ion mass spectrometry, 291, 292, 311, 318

532 Singly-charged anions, 6 Singly-charged ions, large, 17 Skimmer lens, 105 Slides, glass, 431 Slides, indium–tin oxide coated glass, 422 Slides, non-conductive plain glass, 422 Small molecule analysis, 419 Small molecule identification, 430 S-methyl 5,5′-thiodipentanoylhydroxysuccinimide, 106, 108 structure, 107 SN2 displacement, 400 Sodium, 425 Sodium acetate, 425 Sodium adduct ion, 431, 433 Sodium dodecyl sulfate polyacrylamide gel electrophoresis, SDS-PAGE, 101, 154 Sodium ion adduct, 423 Sodium phosphocholine, 427 Solid-phase isotope-labeling strategy, 96 Solvents, chlorinated, 492 Sonic spray ionization, SSI, 11, 62 SORI-CID, 122, 130, 132, 133, 135, 246 principles of, 132, 133 Source region, 105, 387, 389 corona discharge, 389 radioactive nickel foil, 389 ultraviolet discharge lamps, 389 Source, switchable, 447 Space charge, 467 control, 417, 422 interaction, 189 limit, 240 limited density, 174 Space-charging, 423, 424 Spatial resolution, 422 Spatially-resolved measurement, 293 Spectrograph, Shamrock 303i, Andor Technologies, 257 Spectroscopy, action (or consequence), 240, 241 Sphingomyelin, SPM, 425, 432, 433 Spinal cord, 432 Splenic tissue, cryosectioned, 435 Sprague-Dawley rat, 425 Spring constant, 302 Sr+, 355 SSI, 12 Stability diagram, 26, 268, 270, 348, 351, 353, 369–371, 373, 375, 382, 383, 385 boundaries of, 350, 352, 378, 382 computed and experimentally-determined, 380, 381 cross-section of, 351 theoretical, 374 Stability region, 298, 378 first, 378

Subject Index Stability, instrumental, 505 Stability, reliability, 505 Stable isotope labeling by amino acids in cell culture, SILAC, 94 Stable isotope labeling strategies, summary, 95 Stable trajectory region, 380 Stacked-ring ion guide, SRIG, 210 Stark shift, 359 Stearic acid, 426 Stilbene, 36 Stored waveform inverse Fourier transform, SWIFT, 131, 174–176, 191, 458–460 Streptavidin affinity chromatography, 86 Strong cation exchange (SCX) chromatography, 86 Strontium ion, 346 Structural characterization, 425 Styrene, 495, 497, 500 Sub-Doppler laser cooling, 341 Substatia nigra, 425 Sulfonium ion derivatization, 92 Sulfur dioxide, 6 Sulfur hexafluoride, 407 Supersonic jet, 245 Supplemental fields, dipole, 442, 462, 464 Supplemental fields, quadrupole, 442 Supplemental waveform, 66 Supplementary radiofrequency voltage, 347, 367 Supplementary RF signal, 16 Surface charge, 339 Surface waters, pollution of, 503 Surface-induced dissociation, SID, 130 Sustained off-resonance irradiation CID, see SORI-CID Swarm experiments, 407 Sweep frequencies, 369 Switching circuits, 374 Sympathetic cooling, 292, 300, 356, 360 Sympathetically-cooled single ion mass spectrometry, SCSI-MS, 292, 293, 295, 296, 299, 300, 303, 305, 309, 311, 312, 321, 323, 324 Synapt high definition mass spectrometer, HDMS, 210 Synapt instrument, 212, 215, 218, 221, 223–230 Synapt, modes of operation, 213 schematic diagram, 211 Syrian Hamster protein, 214 Syrian Hamster PrP protein, 220

T Taggants, 399 Tailored waveform, 16 Tandem mass spectrometric analysis, 96, 97

Subject Index Tandem mass spectrometric strategy, 105 Tandem mass spectrometry, 59, 87, 89, 91, 92, 104, 105, 122, 130, 367, 372, 417, 419, 424–428, 434–436 analysis, 97, 153–164, 214, 224, 226, 230 multiple stages of, 9, 14, 61, 62, 72, 83, 84, 105–107, 133, 212, 226, 367, 425, 426, 430–432, 436 functionality, 25 interrogation scheme, 64 scan type, 61 scan, 100 Tandem-in-space, 454 Tandem-in-time, 5, 454 Tantalum, 345, 346 Tekmar velocity XPT purge and trap, 496 Terahertz (THz) frequency domain, 329 Terephthalic acid, 48 Tetrachloroethylene, 492, 495, 501, 504 Tetrameric transthyretin (TTR) complex, 222 Tetramethylrhodamine, 191 Thermal equilibrium, 388 Thermalization, 389 Thermo Electron Corporation, 420 Thermo Finnigan LCQ mass spectrometer, 42, 43 Thermo Scientific, 440 Thermo Scientific ITQ, 447 Thermodyamic data, 387, 391, 394, 397, 398 Three-dimensional (3D) quadrupole ion trap, 5 Tickle activation, 347, 348, 372 Tickle frequency, 348, 349 Tickle voltage, 347, 348, 372 Time metrology, 328, 341, 359 Time-domain signal, 126, 207 Time-of-flight mass spectrometer, 293, 295, 419 Time-of-flight, TOF, 9, 211 Time-of-flight/time-of-flight, TOF/TOF, 97 Time-resolved measurement, 293 TiO2, 86 Tissue analysis, 417, 422 Tissue sample, 421, 429 Tissue section(s), 418, 430, 431, 433, 435 Tissue specimens, 424 Tissue studies, 423 Tissue surface, 419 Tissue, intact, 426 ovarian, 419 TMPP-Ac derivative, 90 TMPP-Ac-OSu, 88 TMPP-AcSC6F5 bromide, 88, 89 TOF, 12 TOF mass analyzer, 14, 171, 172, 208 TOF mass spectrum, 174 TOF, orthogonal acceleration, 225 TOF, see Time-of-flight mass spectrometer Toluene, 492, 495, 498, 501–504

533 Torus, 345 Total ion chromatogram, TIC, 472, 473, 476–478, 483, 484 Total ion count, TIC, 423 Total organic carbon, TOC, 483 Toxicological drug study, 435 Transcriptional editing process, 59 Transferrin, 141 Transition metal complex cations, 20 Transition metal ion insertion, 20 Transition, fluorescence of, 330 Transmission mode ETD, 23 Trap ring aperture, 188 diameter, 188 Trapped ion cloud, 135 Trapped ion electron diffraction, TIED, 169–171, 173 Trapped ion fluorescence, 186 spectroscopy, 187, 241 Trapped ion instrument, 60 Trapped ion laser excitation, 187 Trapped ion mass spectrometer, 72, 240–245, 247, 254, 282, 283 Trapped ions, 333 activated by IR laser, 54 dynamics, 169–199, 348 structure, 169–199 Trapping by proxy, 5 Trapping field imperfection, 316 Trapping field, hexapolar component of, 263 Trapping frequency calibration, 456 Trapping oscillation, 124 Trapping parameters, 349, 369 Trapping, selective, 456 Traps on micro-chips, 328 Traveling wave IMS, TWIMS, 206, 209, 212, 213, 215–225, 228 Traveling wave ion guide, TWIG, 209–212 Traveling wave, T-Wave, 209–212 Tributylamine, 220 Trichloroethylene, 492, 495, 498, 502–505 Triethylene, 220 Trihalomethanes, 492 Triple-stage quadrupole, 367–369, 427 /LIT mass spectrometer, 11 TriWave, 210, 211, 215 trp RNA binding protein, TRAP, 219 Trp-11 neurotensin, 20 Trp-cage protein charge states, 192 Tryptic lectin glycopeptide, 23 Tryptic peptide, 208 Tryptic protein digest, 219 Tryptophan, Trp, 186, 191, 219 Tumor detection, 419 Turning quadrupole, 6–8 T-wave, 211, 215, 216; see also Traveling wave IMS, TWIMS

534

Subject Index

Two-dimensional differential gel electrophoresis, 2D DIGE, 93 Two-ion crystal, 305 system, 300, 305, 319, 321, 323

vMALDI, see Matrix-assisted laser desorption, intermediate vacuum Volatile organic compounds, VOCs, 492–494, 499, 505

U

W

U.S. Environmental Protection Agency, USEPA, Method, 492 U.S. Naval Observatory, 329 U.S. Navy Observatory, USNO, 354 Ubiquitin, 54, 69, 126, 133 Ultra low expansion, ULE, spacer, 356, 357 Ultra-violet photon dissociation, UVPD, 41 Undersampling, 422 Unipolar mode excitation, 348 Universal constant, 330 Unstable, 368 Upper m/z limit, 14 Urinary metabolites, 208 USEPA Method 505, 484, 485 USEPA Method 521, 439, 470, 472, 481, 483, 484 USEPA Method 524.2, 470 USEPA Method 525.2, 469 USEPA Method 527, 470 USEPA Method 528, 470 USEPA Method 529, 470 USEPA Method 603, 498 USEPA Method 8260, 470 USEPA Method 8260B, 495–497, 505 USEPA Method 8270, 439, 468–470, 473, 475 USEPA Method SW-846, 470 USEPA Methods, 439, 467 USEPA, see U.S. Environmental Protection Agency UV photodissociation, 93

Wannier expression, 391 Wastewater(s), 497, 499, 502, 503 Water, 396, 405 drinking, 483, 492 industrial, 501 reagent, 486 surface, 486 Waters Corporation, 210, 213 Waveform, broadband, 456 Waveform, notch, 456, 457, 460–462 Wine, 153 Wine astringency, 153, 154, 164 Wine tasting, 155 Wine, organoleptic property, 153 Wire mesh, micrometric, 347 Working points, 371

V Van der Waals complex, 243 Van’t Hoff plot, 396, 399, 400 Varian 4000 ion trap, 442 Varian 4000MS, 449–451, 454 Varian 500MS, 444 Varian quadrupole ion trap mass spectrometer, 494 Varian Saturn, 440 Varian Star 3400X Saturn 2000 GC/MS, 496 Varian turbo DDS, 464 Velocity of light, 330 Vial shield, 450 Vibrational relaxation, 176 Vibrational temperature, 171 Vinblastine, 225 Vinyl chloride, 502 Virus capsids, 220 Virus tails, 220 Viscous damping force, 303, 345

X Xenon cations, 21 X-ray, 173, 221 scattering, 219 Xylene(s), 492, 500

Y Yb+, 355 Yeast enolase, tryptic digest, 91, 92 Ytterbium, 332, 334

Z z0, 173, 296 Zeeman effect, 354, 357, 359 Zidovudine, 228 Zoom scan mode, 443 ZrO2, 86 Z-spray source., 210, 211 Zwitterion, 247, 249 α-Helical PrP, 220 α-Helical PrP, β-sheet-rich structures, 220 α-Methylstyrene, 500 β-Casein phosphopeptide, 137 β-Galactosidase, 141 β-Lactoglobulin, 54 βr, 370, 372, 373, 380, 382 βu, 261, 262 βx, 350, 352, 353 βz, 268, 270–272, 276, 350–353, 370, 382, 383, 385 μ-Metal shield, 172