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Ion Trap Mass Spectrometers*
Ion Trap Mass Spectrometers Raymond E March, Trent University, Peterborough, Ontario, Canada & 2010 Elsevier Ltd. All rights reserved. This article is reproduced from the previous edition, volume 2, pp 1000–1009, & 1999, Elsevier Ltd., with revisions made by the Editor.
Symbols au D¯r D¯z m n qu r0 u U V z0 bz n x X
dimensionless trapping parameter (u ¼ r or z) depth of potential well in radial direction depth of potential well in axial direction ion mass [amu] order of frequency component dimensionless trapping parameter (u ¼ r or z) radius of ring electrode collective coordinate axes r and z DC potential 0-to-peak amplitude of the RF potential half the separation of the end-cap electrodes, along the axis of cylindrical symmetry trapping parameter ¼ (az þ qz2/2)1/2 a dimensionless parameter ¼ Ot/2 fundamental frequency component radial frequency of the applied RF potential
Introduction An ion trap mass spectrometer functions both as a mass spectrometer of considerable mass range and variable mass resolution and as an ion store in which gaseous ions can be confined. Unlike other mass spectrometers that operate at pressures o106 Torr, the ion trap operates at 1 mTorr of helium. As a storage device, the ion trap acts as an ‘electric-field test-tube’ for the confinement of gaseous ions either positively charged or negatively charged. The confining capacity of the ion trap arises from a trapping potential well formed when appropriate potentials are applied to the ion trap electrodes. The ion trap functions as a mass spectrometer when the trapping field is changed, so that the trajectories of simultaneously trapped ions of consecutive specific mass/charge ratio become sequentially unstable, and ions leave the trapping field in order of mass/charge ratio. Upon ejection from the ion trap, ions strike a detector and provide an output signal. With the advent of new methods by which gaseous ions can be formed from polar molecules and injected into an ion trap, a wider range of ion trap applications is possible. The coupling of liquid chromatography (LC) with electrospray (ES) ionization and with mass
spectrometry (MS) in the early 1980s led to the development of new ion trap instruments for the analysis of nonvolatile, polar and thermally labile compounds. In 1995, new ion trap instruments (Finnigan’s LCQ and GCQ , and Bruker’s ESQUIRE) were introduced, which employ external ion sources with injection of ions into the ion trap. The major focus for the application of these instruments, using LC-ES/MS, is the examination of high-molecular-mass biopolymers such as proteins, peptides and oligodeoxyribonucleotides. Several more ion trap devices have recently been developed but are outside the scope of this article, which only covers 3-D or Paul-type ion trap mass spectrometers. Linear ion trap derivatives of this technology were developed early this century. These devices offer advantages of higher ion capacity and sensitivity. The advent of orbital trapping techniques also took hold in this same time period, the resultant Orbitrap instruments offer resolution 4100 000 with a purely electrostatic type of mass spectrometer. While these devices are not treated in this article, suggested reading for them are provided at the end.
The Quadrupole Ion Trap Mass Spectrometer The quadrupole ion trap consists of three electrodes which are shown in open array in Figure 1. Two of the electrodes are virtually identical and, while having hyperboloidal geometry, resemble small inverted saucers; these saucers are end-cap electrodes and are distinguishable by the number of holes in the centre of each electrode. One end-cap electrode has a single aperture through which electrons and/or ions can be gated, while the other has several apertures arranged centrally and through which ions pass to a detector. The third electrode, also of hyperboloidal geometry but of two sheets rather than one, is the ring electrode; it resembles a napkin holder and is of similar size, since the radius, r0, in the central plane is B1 cm. The ring electrode is positioned symmetrically between two end-cap electrodes as shown in Figure 2; Figure 2a is a photograph of an ion trap cut in half along the axis of cylindrical symmetry, while Figure 2b is a cross section of an ideal ion trap showing the asymptotes and the dimensions r0 and z0,
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Ion Trap Mass Spectrometers
Figure 1 The three electrodes of the quadrupole ion trap shown in open array.
where 2z0 is the separation of the end-cap electrodes along the axis of the ion trap. The electrodes in Figure 2 are truncated for practical purposes but, in theory, they extend to infinity and meet the asymptotes shown. The electrode geometries are defined so that, when an RF potential is applied to the ring electrode with the end-cap electrodes grounded, a near-ideal quadrupole field is produced, which creates a parabolic potential well for ion confinement, Figure 3. As shown in Figure 3, the potential well in the axial ¯ z, while that in the radial direction direction is of depth D ¯Dr ; since D ¯ zE2D ¯ r, the potential well resembles more a flower vase than a bowl. Mass-selective ejection of ions from the potential well is accomplished by linearly ramping the amplitude of the RF potential; each ion species is ejected at a specific RF amplitude and, since the initial amplitude and ramping rate are known, the mass/charge ratio can be determined for each ion species. This method for measuring mass/ charge ratios of confined ions was developed by Stafford and is known as the ‘mass-selective axial instability mode’; this method made possible the commercialization of the ion trap in the early 1980s. A prerequisite is that ions be focused initially to the ion trap centre by momentum-dissipating collisions with helium atoms.
History and Literature The history of the quadrupole ion trap originates in the pioneering work of Paul and Steinwedel in the mid1950s; their work was recognized by the award of the 1989 Nobel Prize in Physics to Wolfgang Paul. Yet the basis of the theory of operation of quadrupole devices was laid down over 140 years ago by Mathieu, from his investigation of vibrating stretched skins.
Figure 2 Quadrupole ion trap. (a) Photograph of an ion trap cut in half along the axis of cylindrical symmetry. (b) Schematic diagram of the three-dimensional ideal ion trap showing the asymptotes and the dimensions r0 and z0.
Those papers that are landmarks in this field are listed in the bibliography together with the five texts in which are described a wide variety of applications of the ion trap. The history of this device has been expressed as several ‘ages’, beginning with mass-selective detection; this age, which covered the 1950s and began with disclosure of quadrupolar devices by Paul and Steinwedel,
Ion Trap Mass Spectrometers
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structure differentiation, ion photodissociation, lasers and the ion trap, and ion traps in the study of Physics. Volume 3, subtitled ‘Chemical, Environmental and Biomedical Applications’, includes a revisitation of fundamentals and expositions on gas chromatography–ion trap tandem mass spectrometry (GC–MS/MS) and liquid chromatography-ion trap tandem mass spectrometry (LC–MS/MS). More recently, an introduction to the quadrupole ion trap written in a tutorial form has been published. An excellent source of information is the publication entitled Proceedings of the Annual Conference of the American Society for Mass Spectrometry and Allied Topics. Figure 3 Representation of the parabolic trapping potential ¯ z and D ¯ r. wells of depths D
included the storage of microparticles by Wuerker, Shelton and Langmuir and the first use of the ion trap as a mass spectrometer by Fischer. The second age is described as mass-selective storage and covers the period 1962–82. Detailed accounts of the development of the quadrupole-type devices during the early part of this period have been published by Dawson and Whetten and by Dawson; this latter publication has been reprinted in the series of ‘American Vacuum Society Classics’ by the American Institute of Physics under ISBN 1563964554. The third age (1983–88) is described as mass-selective ejection; this age ushered in the commercialization of the ion trap as a mass-selective detector for gas chromatograph and was a period of intense activity. In 1989, the present age of recent advances and developments commenced with the recognition of the work of Wolfgang Paul and Hans G. Dehmelt by the award, in part, of the Nobel Prize in Physics. In the same year, an account of the ion trap together with a full treatment of ion trap theory appeared in the text Quadrupole Storage Mass Spectrometry by March, Hughes and Todd; the historical account in this text by Todd was expanded into a fullscale review. Other reviews have been contributed by Cooks and co-workers and a special collection reporting upon recent developments has also appeared. Ion trap mass spectrometry was reviewed for the 12th International Mass Spectrometry Conference in 1991. In 1995, three volumes entitled Practical Aspects of Ion Trap Mass Spectrometry were published in the CRC Series, Modern Mass Spectrometry. Volume 1 of this series, subtitled ‘Fundamentals of Ion Trap Mass Spectrometry’, covers the history of the ion trap, nonlinear ion traps, ion activation, ion–molecule reactions and ion trajectory simulations; the reader is referred to chapter 1 for a discussion of the Ages of the Quadrupole Ion Trap and to chapter 2 for an exposition of the mathematical basis of ion trap operation. Volume 2, subtitled ‘Ion Trap Instrumentation’, deals with enhancement of ion trap performance, confinement of externally generated ions, ion
The Trapping Potential Well The trapping potential well created within the electrode assembly of an ion trap is of parabolic cross section; ion species are confined in layers in the well rather like an exotic drink of several liqueurs arranged carefully in horizontal layers according to their density, as shown in Figure 4a. However, the ions of lowest mass/charge ratio reside at the ion trap centre (bottom of the well) surrounded, like the centre of an onion, by layers of ions of increasing mass/charge ratio. Upon tilting the bowl to the right, equivalent to ramping the RF trapping potential, the layer of least density, corresponding to ions of highest mass/charge ratio, will be poured from the well. To withdraw the layer of greatest density, that is, ions of lowest mass/charge ratio, a ‘straw’ is introduced and the bottom layer is sucked out as shown in Figure 4b; the straw represents axial modulation (see below) and the liqueur glass in Figure 4b corresponds to the detector. For an ideal quadrupole field, the following identity is given, r 20 ¼ 2z 20
½1
so that once the magnitude of r0 is given the sizes of all three electrodes and the electrode spacings are fixed; in the majority of commercial ion traps, r0 lies in the range 0.7–1.0 cm.
The Theory of Ion Trap Operation The motions of ions in quadrupole devices differ markedly from those in magnetic and electrostatic sectors. The quadrupole ion trap is described as a dynamic instrument since ion trajectories are influenced by timedependent forces. An Ion in a Quadrupole Field An ion in a quadrupole field experiences strong focusing in that the restoring force, which drives the ion back
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Figure 4 (a) Schematic presentation of a trapping parabolic potential well where the three liquids differing in density represent ions differing in mass/charge ratio. (b) The tilting of the well corresponds to ramping of the RF potential while the straw, with which ions are withdrawn in order of increasing mass/charge ratio, represents axial modulation.
towards the centre of the device, increases as the ion deviates from the centre. The resulting ion trajectories resemble Lissajous figures (figures-of-eight) and the motion of ions is described mathematically by the solutions to the second-order linear differential equation described originally by Mathieu from his investigation of the mathematics of vibrating stretched skins. He described solutions in terms of regions of stability and instability; these solutions and the criteria for stability and instability also describe the trajectories of ions confined in quadrupole devices and define the limits to trajectory stability.
where U is a DC potential and V is the amplitude of the RF potential of the form Vcos Ot. It is seen that az ¼ 2ar and qz ¼ 2qr . Since U ¼ 0, ar and az are equal to zero and the common mode of ion trap operation corresponds to operation on the qz axis of the stability diagram. The expression for qz contains the mass/charge ratio for a given ion, the size of the ion trap, r0, the amplitude V of the RF potential and the radial frequency O, that is, all of the parameters that are needed to understand the operations of the ion trap. The ‘Stretched’ Ion Trap
The Mathieu Equation The canonical form of the Mathieu equation is d 2u þ ðau 2qu cos 2xÞu ¼ 0 dx 2
½2
where u represents the coordinate axes r and z, x is a dimensionless parameter equal to Ot/2, O (for the ion trap) is the radial frequency of the RF potential applied to the ring and au and qu are dimensionless trapping parameters. For the quadrupole ion trap, the trapping parameters are expressed as ar ¼
4eU ; mr 20 O2
qr ¼
2eV mr 20 O2
½3
az ¼
8eU ; mr 20 O2
qz ¼
4eV mr 20 O2
½4
The ion trap electrodes are truncated in order to obtain a practical instrument, but this truncation introduces higher-order multipole components to the potential. To compensate for these multipole components, the electrodes of commercial devices prior to 1995 were assembled with a ‘stretched’ separation of the end-cap electrodes; the value of z0 was increased by 10.6%. An account of the ‘stretching’ of the ion trap is given by Syka in chapter 4 of volume 1 in the CRC books, while in chapter 3 is presented an account by Franzen, Gabling, Schubert and Wang of nonlinear ion traps. The immediate consequences of stretching are that the asymptotes to the end-cap electrodes no longer coincide with those for the ring electrode, r20a2z20 and the values of the trapping parameters are changed. The trapping parameters are now expressed as ar ¼
8eU ; mðr 20 þ 2z 20 ÞO2
qr ¼
4eV mðr 20 þ 2z 20 ÞO2
½5
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and az ¼
16eU ; mðr 20 þ 2z 20 ÞO2
qz ¼
8eV mðr 20 þ 2z 20 ÞO2
½6
For the ion trap in the LCQ and GCQ instruments, r0 ¼ 0.707 cm and z0 ¼ 0.785 cm, such that the geometry has been stretched by B57%.
Regions of Ion Trajectory Stability Quadrupole ion trap operation is concerned with the criteria that govern the stability of an ion trajectory in both r and z directions within the field, that is, the experimental conditions that determine whether or not an ion is stored. The solutions to Mathieu’s equation are of two types, (i) periodic but unstable, and (ii) periodic and stable. Solutions of type (i) form the boundaries of unstable regions on the stability diagram and correspond to those values of a trapping parameter bz that are integers, that is, 0, 1, 2, 3,y; bz is a complex function of az and qz that is approximated as rffiffiffiffiffiffiffiffiffiffiffiffiffiffi q2 bz ¼ az þ z 2
Figure 5 Several Mathieu stability regions for the threedimensional quadrupole field. (a) Diagrams for the z direction of (az, qz) space. (b) Diagrams for the r direction of (az, qz) space.
½7
for qzo0.4. The boundaries represent, in practical terms, the point at which an ion trajectory becomes unbounded. Solutions of type (ii) determine ion motion in an ion trap. The stability regions corresponding to stable solutions in the z-direction are shaded and labelled z-stable in Figure 5a, while those corresponding to stable solutions in the r-direction are shaded and labelled r-stable in Figure 5b; the latter are doubled in magnitude along the ordinate and inverted. Ions are confined in the ion trap provided their trajectories are stable in the r and z directions simultaneously; such trajectory stability is obtained in the region closest to the origin, that is, region A in Figure 6, which is plotted in au, qu space, that is, where au is plotted against qu. Regions A and B are referred to as stability regions; region A is shown in detail in Figure 7. The coordinates of the stability region in Figure 7 are the parameters az and qz. In Figure 7, the bz ¼ 1 stability boundary intersects with the qz axis at qz ¼ 0.908; this intersection is the working point of the ion of lowest mass/charge ratio that can be stored.
Secular Frequencies A three-dimensional representation of an ion trajectory, shown in Figure 8, has the general appearance of a Lissajous curve composed of two fundamental frequency components, or,0 and oz,0, of the secular motion. Higher-order
Figure 6 The Mathieu stability diagram in (az,qz) space for the quadrupole ion trap in both the r and z directions. Regions of simultaneous overlap are labelled A and B.
(n) frequencies exist and the family of frequencies is described by or,n and oz,n as given by ou;n ¼ ðn þ bu =2ÞO;
0r no N
½8
No n o 0
½9
and ou;n ¼ ðn þ bu =2ÞO;
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Figure 9 Pure quadrupole field, or potential surface, for a quadrupole ion trap. Note the four poles of the surface and the similarity of the field shape to the trajectory in Figure 8. Figure 7 Stability diagram in (az,qz) space for the region of simultaneous stability in both r and z directions near the origin for the three-dimensional quadrupole ion trap; the iso-br and iso-bz lines are shown. The qz axis intersects the bz ¼ 1 boundary at qz ¼ 0.908, which corresponds to qmax in the mass-selective instability mode.
the ITSIM simulation program, while the potential surface was generated by calculating the potential for increments of 1 mm in both radial and axial directions.
Resonant Excitation
Figure 8 Trajectory of a trapped ion of m /z 105. The initial position was selected randomly from a population with an initial gaussian distribution (FWHM of 1 mm); qz ¼ 0.3; zero initial velocity. The projection onto the xy plane illustrates planar motion in three-dimensional space. The trajectory develops a shape that resembles a flattened boomerang. Reproduced from Nappi et al. (1997) International Journal of Mass Spectrometry and Ion Processes 161 : 77–85.
The simulated ion trajectory shown in Figure 8 resembles a roller-coaster ride and depicts the motion of an ion on the potential shown in Figure 9. The oscillatory motion of the ion results from the undulations of the potential surface, which can be envisaged as rotating. The simulation of the ion trajectory was carried out using
The motion of confined ions can be excited upon resonant irradiation at oz; resonant excitation is a powerful technique in ion trap mass spectrometry since predetermined waveforms composed of specified frequencies or frequency ranges can be used. Irradiation is effected by applying a supplementary potential of some hundreds of millivolts across the end-cap electrodes. Prior to resonant excitation, ions are focused collisionally to the ion trap centre by collisions with helium atoms. This process is described as ‘ion cooling’ in that ion kinetic energies are reduced to B0.1 eV, corresponding to B800 K. Resonant excitation, or ‘tickling’ of cooled ions, causes ions to move away from the ion trap centre so that they experience the trapping field and are accelerated to kinetic energies of tens of electronvolts. Resonant excitation is used to increase ion kinetic energy for the following purposes. (1) To eject unwanted ions during ionization and to isolate a narrow range of mass/charge ratios. (2) To promote endothermic ion/ molecule reactions. (3) To increase ion internal energy through momentum-exchange collisions with helium atoms; in the limit, ions dissociate. (4) To move ions towards an end-cap electrode where an image current can be detected for their nondestructive measurement and re-measurement. (5) To eject ions either for ion isolation or for mass-selective ejection while the applied frequency is swept. (6) To eject ions while the amplitude V of the main RF potential is ramped up; this mode, known as axial modulation, uses a fixed frequency to
Ion Trap Mass Spectrometers
eject ions just before their trajectories become unstable. In axial modulation, the resonant frequency is slightly less than half the main drive frequency O. Resonant excitation at lower frequencies has been used with great success to extend the normal mass range of the ion trap.
Operation of the Ion Trap as a Mass Spectrometer In the ion trap, gaseous molecules are bombarded with 50–80 eV electrons emitted from a heated filament and gated into the trap, as shown in Figure 10a. Under automatic gain control (AGC), the number of ions formed during 200–ms is used to scale the ionization time and produce the required number of ions. During ionization, an RF voltage V0 is applied to the ring electrode so as to confine ions in a given range of mass/charge ratio. Nascent ions are subjected to about 20 collisions per millisecond with helium at a pressure of 103 torr; those ions that are not ejected become focused near the trap centre. In Figure 10b, an RF amplitude is ramped over the period 30–85 ms, during which mass-selective ion ejection and mass analysis occur. Each ion species confined within the ion trap is associated with a qz value that lies on the qz axis on the stability diagram; ions of high mass/charge ratio have qz values near the origin, while ions of lower mass/charge ratio have qz values that extend towards the bz ¼ 1 stability boundary, as shown diagrammatically using stickpeople of various sizes in Figure 11a. At the intersection of the bz ¼ 1 stability boundary and the qz axis, where qz ¼ 0.908 (see Figure 7), the trajectories of trapped ions become unstable axially and ions leave the ion trap. Once the ion cloud has been focused collisionally to the ion trap centre, the amplitude of the RF potential is ramped; this operation, which is described as an analytical ramp
Figure 10 An overview of MS-in-time. (a) Step 1: a trapping RF amplitude is applied for 0–30 ms during which ions are formed from sample molecules and stored. (b) Step 2: an RF amplitude is ramped over the period 30–85 ms during which mass-selective ion ejection and mass analysis occurs.
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or analytical scan, increases the qz values of all ion species and, when qz ¼ 0.908 for each ion species, the ions are ejected axially through the end-cap electrodes. This mass-selective axial instability method of ion ejection has been supplanted by the use of axial modulation. Originally, axial modulation described resonant ejection of ions at a frequency of 485 kHz and at a qz value slightly less than 0.908. When the RF amplitude is ramped, ions come into resonance at 485 kHz as their qz values approach 0.908 and are ejected axially in order of increasing mass/charge ratio. Since ions are focused near the ion trap centre in the fashion of an onion, resonance ejection has the effect of removing the ions of low mass/ charge ratio residing in the innermost layer of the onion from the influence of space-charge perturbations induced by other ion species, so that ions are ejected free of spacecharge and with enhanced mass resolution. Resonant ejection, which can be carried out over a wide frequency range, is depicted pictorially in Figure 11b, which shows ions residing near the bottom of their respective axial
Figure 11 (a) Schematic representation of working points (that is, coordinates in az,qz space) in the stability diagram for several species of ions stored concurrently. The arrangement of working points with respect to mass/charge ratio is depicted by figures that differ in size. (b) Ions are shown residing near the bottom of ¯ z; the ladder their respective axial potential wells of depth D represents the opportunity for resonant ejection of an ion species.
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¯ z; the ladder represents resopotential wells of depth D nant ejection of an ion species. For axial modulation, the ladder is positioned at a qz value slightly less than 0.908. Resonantly ejected ions pass through holes in both endcap electrodes so that B50% impinge upon an electron multiplier located behind one of the end-cap electrodes; ion signals are created that produce a mass spectrum in order of increasing mass/charge ratio. A mass spectrum is obtained by running the scan function (see below) a number of times specified by the number of microscans; the signals from each microscan are averaged and yield a mass spectrum.
specificity. Under the influence of the tickle voltage, ions are moved from the centre to a region of higher potential, whereupon they are accelerated and their kinetic energies are increased. Subsequent collisions with helium atoms lead to enhancement of ion internal energy. In analytical applications, where the objective is to dissociate all isolated ions and to maximize the trapping of fragment ions produced, ion kinetic energy uptake must be balanced with incremental accumulation of internal energy so that ejection of isolated ions and fragment ions is avoided.
Tandem Mass Spectrometry Scan Function The above operation can be expressed succinctly in a scan function, which shows the temporal variation of the potentials applied to the electrodes such that a scan function is a visual representation of the sequence of program segments in the software that controls ion trap operation. The scan function for the above mass spectrometric operation is shown in Figure 12.
Collision-Induced Dissociation Collision-induced dissociation (CID) of an isolated ion species in a quadrupole ion trap is a powerful technique for both the determination of ion structures and the analytical identification of compounds with high
Tandem (Latin: ‘‘at length’’) mass spectrometry, MS/MS, is the practice of performing one mass-selective operation after another, much as the riders are seated on a tandem bicycle. The first mass-selective operation isolates an ion species designated as the parent ion, while the second determines the mass/charge ratios of the fragment, or product, ions formed by CID of the parent ions. MS/MS with a quadrupole ion trap, where successive mass-selective operations are carried out in time, offers a number of advantages. First, since the ion trap operates in a pulsed mode, mass-selected ions can be accumulated over time. Second, since CID is wrought by many collisions of mass-selected ions with helium atoms wherein the energy transferred per collision is small, dissociation channels of lowest activation energy are accessed almost exclusively. Third, all isolated ions can be dissociated and fragment ions arising from some 90% of them can be confined. Fourth, a sequence of several mass-selective operations can be performed as in MSn. When gas chromatography is interfaced with an ion trap tandem mass spectrometer, individual compounds can be detected at the hundreds of femtograms level. The high specificity or informing power obtainable with GCMS/MS is achieved by observation of specific fragment ion signals from an isolated molecular ion species Mdþ formed from M that elutes within a specified retentiontime window.
Chemical Ionization and Ion Molecule Reactions
Figure 12 Scan function for obtaining an EI mass spectrum. The scan function shows the ionization period, A, followed immediately by the analytical ramp with concurrent axial modulation. Note that the pre-scan for the automatic gain control algorithm is not shown.
In the quadrupole ion trap, several types of reactions can and do occur simultaneously and spontaneously once electron ionization of a compound has occurred. Ion– molecule reactions involving charge transfer, proton transfer and clustering occur sequentially, resulting in the formation of stable even-electron ions. Proton transfer chemical ionization (CI) involves the transfer to a neutral species of a proton (or other even-electron charged particles) from an ion that has been formed in an
Ion Trap Mass Spectrometers
ion–molecule reaction. Common CI reagents are CH5þ and C2H5þ, which are formed rapidly and can be isolated prior to reaction. CI reagent ions can be created externally and injected into the ion trap, isolated massselectively and allowed to react with sample molecules.
Conclusions Ion trap mass spectrometry is a versatile technique of high sensitivity and high specificity. The relatively low cost of commercial instrumentation has permitted a substantial growth in the practice of mass spectrometry. The theory of ion trap operation differs from those of other mass spectrometers and presents an exciting challenge to the mass spectrometry community. See also: Biological Applications of IR, Chemical Ionization in Mass Spectrometry, Chromatography-MS, Methods, Electrospray Ionization in Mass Spectrometry, Fourier-Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICR MS), Ion Molecule Reactions in Mass Spectrometry, Ion Structures in Mass Spectrometry, Mass Spectrometry, Historical Perspective, MS Based Metabonomics, MS–MS and MSn, Proteomics, Proton Affinities Determined Using Mass Spectrometry, Quadrupoles, Use of in Mass Spectrometry
Further Reading Cooks RG and Kaiser RE Jr (1990) Quadrupole ion trap mass spectrometry. Accounts of Chemical Research 23: 213--224. Dawson PH (1976) Quadrupole Mass Spectrometry and Its Applications. Amsterdam: Elsevier. Dawson PH and Whetten NR (1969) Radiofrequency quadrupole mass spectroscopy. Electronics and Electron Physics 27: 58--158. Fischer E (1959) Three-dimensional stabilization of charge carriers in a quadrupole field. Zeitschrift fu¨r Physik 156: 1--26. Glish GL and McLuckey SA (eds.) (1991) Quadrupole Ion Traps ( International Journal of Mass Spectrometry and Ion Processes 106).
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Hardman M and Makarov A (2003) Interfacing the Orbitrap mass analyzer to an electrospray ion source. Analytical Chemistry 75: 1699–1705. Hu O, Noll RJ, Li H, Makarov A, Hardman M, and Cooks RG (2005) The Orbitrap: A new mass spectrometer. Journal of Mass Spectrometry 40: 430–443. Makarov A (2000) Electrostatic axially harmonic orbital trapping: A highperformance technique of mass analysis. Analytical Chemistry 72: 1156–1162. March RE (1992) Ion trap mass spectrometry. International Journal of Mass Spectrometry and Ion Processes 118/119: 71. March RE (1997) An introduction to quadrupole ion trap mass spectrometry. Journal of Mass Spectrometry 32: 351. March RE, Hughes RJ, and Todd JFJ (1989) Quadrupole Storage Mass Spectrometry. New York: Wiley Interscience. March RE and Todd JFJ (eds.) (1995) Practical Aspects of Ion Trap Mass Spectrometry, Modern Mass Spectrometry Series; vol. 1, Fundamentals, ISBN 0-8493-4452-2; vol. 2, Instrumentation, ISBN 0-8493-8253-X; vol. 3, Chemical, Biomedical, and Environmental Applications, ISBN 0-8493-8251-3. Boca Raton, FL: CRC Press. Mathieu E (1868) Journal de Mattematiques Pures et Applies (J. Liouville) 13: 137. (See also McLachan NW (1947) Theory and Applications of Mathieu Functions. Oxford: Clarendon Press and Campbell R (1955) The´orie Ge´ne´rale de l’Equation de Mathieu. Paris: Masson. Nappi M, Weil C, Cleven CD, Horn LA, Wollnik H, and Cooks RG (1997) Visual representations of simulated three-dimensional ion trajectories in an ion trap mass spectrometer. International Journal of Mass Spectrometry and Ion Processes 161: 77--85. Nourse BD and Cooks RG (1990) Aspects of recent developments in ion trap mass spectrometry. Analytica Chimica Acta 228: 1--11. Paul W (1990) Electromagnetic traps for charged and neutral particles (Nobel Lecture). Angewandte Chemie 29: 739--748. Paul W and Steinwedel H (1960) Apparatus for separating charged particles of different specific charges. German Patent 944 900, 1056; US Patent 2 939 952. Reiser HP, Kaiser RE Jr, and Cooks RG (1992) A versatile method of simulation of the operating of ion trap mass spectrometers. International Journal of Mass Spectrometry and Ion Processes 121: 49--63. Schwartz JC, Senko MW, and Syka JEP (2002) A two-dimensional quadrupole ion trap mass spectrometer. Journal of the American Society for Mass Spectrometry 13: 659--669. Stafford GC Jr, Kelley PE, Syka JEP, Reynolds WE, and Todd JFJ (1984) Recent improvements in and analytical applications of advanced ion trap technology. International Journal of Mass Spectrometry and Ion Processes 60: 85--98. Todd JFC (1991) Mass Spectrometry Reviews 10: 3. Wuerker RF, Shelton H, and Langmuir RV (1959) Journal of Applied Physics 30: 324.
Symbols au D¯r D¯z m n qu r0 u U V z0 bz n x X
dimensionless trapping parameter (u ¼ r or z) depth of potential well in radial direction depth of potential well in axial direction ion mass [amu] order of frequency component dimensionless trapping parameter (u ¼ r or z) radius of ring electrode collective coordinate axes r and z DC potential 0-to-peak amplitude of the RF potential half the separation of the end-cap electrodes, along the axis of cylindrical symmetry trapping parameter ¼ (az þ qz2/2)1/2 a dimensionless parameter ¼ Ot/2 fundamental frequency component radial frequency of the applied RF potential
Introduction An ion trap mass spectrometer functions both as a mass spectrometer of considerable mass range and variable mass resolution and as an ion store in which gaseous ions can be confined. Unlike other mass spectrometers that operate at pressures o106 Torr, the ion trap operates at 1 mTorr of helium. As a storage device, the ion trap acts as an ‘electric-field test-tube’ for the confinement of gaseous ions either positively charged or negatively charged. The confining capacity of the ion trap arises from a trapping potential well formed when appropriate potentials are applied to the ion trap electrodes. The ion trap functions as a mass spectrometer when the trapping field is changed, so that the trajectories of simultaneously trapped ions of consecutive specific mass/charge ratio become sequentially unstable, and ions leave the trapping field in order of mass/charge ratio. Upon ejection from the ion trap, ions strike a detector and provide an output signal. With the advent of new methods by which gaseous ions can be formed from polar molecules and injected into an ion trap, a wider range of ion trap applications is possible. The coupling of liquid chromatography (LC) with electrospray (ES) ionization and with mass
spectrometry (MS) in the early 1980s led to the development of new ion trap instruments for the analysis of nonvolatile, polar and thermally labile compounds. In 1995, new ion trap instruments (Finnigan’s LCQ and GCQ , and Bruker’s ESQUIRE) were introduced, which employ external ion sources with injection of ions into the ion trap. The major focus for the application of these instruments, using LC-ES/MS, is the examination of high-molecular-mass biopolymers such as proteins, peptides and oligodeoxyribonucleotides. Several more ion trap devices have recently been developed but are outside the scope of this article, which only covers 3-D or Paul-type ion trap mass spectrometers. Linear ion trap derivatives of this technology were developed early this century. These devices offer advantages of higher ion capacity and sensitivity. The advent of orbital trapping techniques also took hold in this same time period, the resultant Orbitrap instruments offer resolution 4100 000 with a purely electrostatic type of mass spectrometer. While these devices are not treated in this article, suggested reading for them are provided at the end.
The Quadrupole Ion Trap Mass Spectrometer The quadrupole ion trap consists of three electrodes which are shown in open array in Figure 1. Two of the electrodes are virtually identical and, while having hyperboloidal geometry, resemble small inverted saucers; these saucers are end-cap electrodes and are distinguishable by the number of holes in the centre of each electrode. One end-cap electrode has a single aperture through which electrons and/or ions can be gated, while the other has several apertures arranged centrally and through which ions pass to a detector. The third electrode, also of hyperboloidal geometry but of two sheets rather than one, is the ring electrode; it resembles a napkin holder and is of similar size, since the radius, r0, in the central plane is B1 cm. The ring electrode is positioned symmetrically between two end-cap electrodes as shown in Figure 2; Figure 2a is a photograph of an ion trap cut in half along the axis of cylindrical symmetry, while Figure 2b is a cross section of an ideal ion trap showing the asymptotes and the dimensions r0 and z0,
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Ion Trap Mass Spectrometers
Figure 1 The three electrodes of the quadrupole ion trap shown in open array.
where 2z0 is the separation of the end-cap electrodes along the axis of the ion trap. The electrodes in Figure 2 are truncated for practical purposes but, in theory, they extend to infinity and meet the asymptotes shown. The electrode geometries are defined so that, when an RF potential is applied to the ring electrode with the end-cap electrodes grounded, a near-ideal quadrupole field is produced, which creates a parabolic potential well for ion confinement, Figure 3. As shown in Figure 3, the potential well in the axial ¯ z, while that in the radial direction direction is of depth D ¯Dr ; since D ¯ zE2D ¯ r, the potential well resembles more a flower vase than a bowl. Mass-selective ejection of ions from the potential well is accomplished by linearly ramping the amplitude of the RF potential; each ion species is ejected at a specific RF amplitude and, since the initial amplitude and ramping rate are known, the mass/charge ratio can be determined for each ion species. This method for measuring mass/ charge ratios of confined ions was developed by Stafford and is known as the ‘mass-selective axial instability mode’; this method made possible the commercialization of the ion trap in the early 1980s. A prerequisite is that ions be focused initially to the ion trap centre by momentum-dissipating collisions with helium atoms.
History and Literature The history of the quadrupole ion trap originates in the pioneering work of Paul and Steinwedel in the mid1950s; their work was recognized by the award of the 1989 Nobel Prize in Physics to Wolfgang Paul. Yet the basis of the theory of operation of quadrupole devices was laid down over 140 years ago by Mathieu, from his investigation of vibrating stretched skins.
Figure 2 Quadrupole ion trap. (a) Photograph of an ion trap cut in half along the axis of cylindrical symmetry. (b) Schematic diagram of the three-dimensional ideal ion trap showing the asymptotes and the dimensions r0 and z0.
Those papers that are landmarks in this field are listed in the bibliography together with the five texts in which are described a wide variety of applications of the ion trap. The history of this device has been expressed as several ‘ages’, beginning with mass-selective detection; this age, which covered the 1950s and began with disclosure of quadrupolar devices by Paul and Steinwedel,
Ion Trap Mass Spectrometers
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structure differentiation, ion photodissociation, lasers and the ion trap, and ion traps in the study of Physics. Volume 3, subtitled ‘Chemical, Environmental and Biomedical Applications’, includes a revisitation of fundamentals and expositions on gas chromatography–ion trap tandem mass spectrometry (GC–MS/MS) and liquid chromatography-ion trap tandem mass spectrometry (LC–MS/MS). More recently, an introduction to the quadrupole ion trap written in a tutorial form has been published. An excellent source of information is the publication entitled Proceedings of the Annual Conference of the American Society for Mass Spectrometry and Allied Topics. Figure 3 Representation of the parabolic trapping potential ¯ z and D ¯ r. wells of depths D
included the storage of microparticles by Wuerker, Shelton and Langmuir and the first use of the ion trap as a mass spectrometer by Fischer. The second age is described as mass-selective storage and covers the period 1962–82. Detailed accounts of the development of the quadrupole-type devices during the early part of this period have been published by Dawson and Whetten and by Dawson; this latter publication has been reprinted in the series of ‘American Vacuum Society Classics’ by the American Institute of Physics under ISBN 1563964554. The third age (1983–88) is described as mass-selective ejection; this age ushered in the commercialization of the ion trap as a mass-selective detector for gas chromatograph and was a period of intense activity. In 1989, the present age of recent advances and developments commenced with the recognition of the work of Wolfgang Paul and Hans G. Dehmelt by the award, in part, of the Nobel Prize in Physics. In the same year, an account of the ion trap together with a full treatment of ion trap theory appeared in the text Quadrupole Storage Mass Spectrometry by March, Hughes and Todd; the historical account in this text by Todd was expanded into a fullscale review. Other reviews have been contributed by Cooks and co-workers and a special collection reporting upon recent developments has also appeared. Ion trap mass spectrometry was reviewed for the 12th International Mass Spectrometry Conference in 1991. In 1995, three volumes entitled Practical Aspects of Ion Trap Mass Spectrometry were published in the CRC Series, Modern Mass Spectrometry. Volume 1 of this series, subtitled ‘Fundamentals of Ion Trap Mass Spectrometry’, covers the history of the ion trap, nonlinear ion traps, ion activation, ion–molecule reactions and ion trajectory simulations; the reader is referred to chapter 1 for a discussion of the Ages of the Quadrupole Ion Trap and to chapter 2 for an exposition of the mathematical basis of ion trap operation. Volume 2, subtitled ‘Ion Trap Instrumentation’, deals with enhancement of ion trap performance, confinement of externally generated ions, ion
The Trapping Potential Well The trapping potential well created within the electrode assembly of an ion trap is of parabolic cross section; ion species are confined in layers in the well rather like an exotic drink of several liqueurs arranged carefully in horizontal layers according to their density, as shown in Figure 4a. However, the ions of lowest mass/charge ratio reside at the ion trap centre (bottom of the well) surrounded, like the centre of an onion, by layers of ions of increasing mass/charge ratio. Upon tilting the bowl to the right, equivalent to ramping the RF trapping potential, the layer of least density, corresponding to ions of highest mass/charge ratio, will be poured from the well. To withdraw the layer of greatest density, that is, ions of lowest mass/charge ratio, a ‘straw’ is introduced and the bottom layer is sucked out as shown in Figure 4b; the straw represents axial modulation (see below) and the liqueur glass in Figure 4b corresponds to the detector. For an ideal quadrupole field, the following identity is given, r 20 ¼ 2z 20
½1
so that once the magnitude of r0 is given the sizes of all three electrodes and the electrode spacings are fixed; in the majority of commercial ion traps, r0 lies in the range 0.7–1.0 cm.
The Theory of Ion Trap Operation The motions of ions in quadrupole devices differ markedly from those in magnetic and electrostatic sectors. The quadrupole ion trap is described as a dynamic instrument since ion trajectories are influenced by timedependent forces. An Ion in a Quadrupole Field An ion in a quadrupole field experiences strong focusing in that the restoring force, which drives the ion back
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Figure 4 (a) Schematic presentation of a trapping parabolic potential well where the three liquids differing in density represent ions differing in mass/charge ratio. (b) The tilting of the well corresponds to ramping of the RF potential while the straw, with which ions are withdrawn in order of increasing mass/charge ratio, represents axial modulation.
towards the centre of the device, increases as the ion deviates from the centre. The resulting ion trajectories resemble Lissajous figures (figures-of-eight) and the motion of ions is described mathematically by the solutions to the second-order linear differential equation described originally by Mathieu from his investigation of the mathematics of vibrating stretched skins. He described solutions in terms of regions of stability and instability; these solutions and the criteria for stability and instability also describe the trajectories of ions confined in quadrupole devices and define the limits to trajectory stability.
where U is a DC potential and V is the amplitude of the RF potential of the form Vcos Ot. It is seen that az ¼ 2ar and qz ¼ 2qr . Since U ¼ 0, ar and az are equal to zero and the common mode of ion trap operation corresponds to operation on the qz axis of the stability diagram. The expression for qz contains the mass/charge ratio for a given ion, the size of the ion trap, r0, the amplitude V of the RF potential and the radial frequency O, that is, all of the parameters that are needed to understand the operations of the ion trap. The ‘Stretched’ Ion Trap
The Mathieu Equation The canonical form of the Mathieu equation is d 2u þ ðau 2qu cos 2xÞu ¼ 0 dx 2
½2
where u represents the coordinate axes r and z, x is a dimensionless parameter equal to Ot/2, O (for the ion trap) is the radial frequency of the RF potential applied to the ring and au and qu are dimensionless trapping parameters. For the quadrupole ion trap, the trapping parameters are expressed as ar ¼
4eU ; mr 20 O2
qr ¼
2eV mr 20 O2
½3
az ¼
8eU ; mr 20 O2
qz ¼
4eV mr 20 O2
½4
The ion trap electrodes are truncated in order to obtain a practical instrument, but this truncation introduces higher-order multipole components to the potential. To compensate for these multipole components, the electrodes of commercial devices prior to 1995 were assembled with a ‘stretched’ separation of the end-cap electrodes; the value of z0 was increased by 10.6%. An account of the ‘stretching’ of the ion trap is given by Syka in chapter 4 of volume 1 in the CRC books, while in chapter 3 is presented an account by Franzen, Gabling, Schubert and Wang of nonlinear ion traps. The immediate consequences of stretching are that the asymptotes to the end-cap electrodes no longer coincide with those for the ring electrode, r20a2z20 and the values of the trapping parameters are changed. The trapping parameters are now expressed as ar ¼
8eU ; mðr 20 þ 2z 20 ÞO2
qr ¼
4eV mðr 20 þ 2z 20 ÞO2
½5
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and az ¼
16eU ; mðr 20 þ 2z 20 ÞO2
qz ¼
8eV mðr 20 þ 2z 20 ÞO2
½6
For the ion trap in the LCQ and GCQ instruments, r0 ¼ 0.707 cm and z0 ¼ 0.785 cm, such that the geometry has been stretched by B57%.
Regions of Ion Trajectory Stability Quadrupole ion trap operation is concerned with the criteria that govern the stability of an ion trajectory in both r and z directions within the field, that is, the experimental conditions that determine whether or not an ion is stored. The solutions to Mathieu’s equation are of two types, (i) periodic but unstable, and (ii) periodic and stable. Solutions of type (i) form the boundaries of unstable regions on the stability diagram and correspond to those values of a trapping parameter bz that are integers, that is, 0, 1, 2, 3,y; bz is a complex function of az and qz that is approximated as rffiffiffiffiffiffiffiffiffiffiffiffiffiffi q2 bz ¼ az þ z 2
Figure 5 Several Mathieu stability regions for the threedimensional quadrupole field. (a) Diagrams for the z direction of (az, qz) space. (b) Diagrams for the r direction of (az, qz) space.
½7
for qzo0.4. The boundaries represent, in practical terms, the point at which an ion trajectory becomes unbounded. Solutions of type (ii) determine ion motion in an ion trap. The stability regions corresponding to stable solutions in the z-direction are shaded and labelled z-stable in Figure 5a, while those corresponding to stable solutions in the r-direction are shaded and labelled r-stable in Figure 5b; the latter are doubled in magnitude along the ordinate and inverted. Ions are confined in the ion trap provided their trajectories are stable in the r and z directions simultaneously; such trajectory stability is obtained in the region closest to the origin, that is, region A in Figure 6, which is plotted in au, qu space, that is, where au is plotted against qu. Regions A and B are referred to as stability regions; region A is shown in detail in Figure 7. The coordinates of the stability region in Figure 7 are the parameters az and qz. In Figure 7, the bz ¼ 1 stability boundary intersects with the qz axis at qz ¼ 0.908; this intersection is the working point of the ion of lowest mass/charge ratio that can be stored.
Secular Frequencies A three-dimensional representation of an ion trajectory, shown in Figure 8, has the general appearance of a Lissajous curve composed of two fundamental frequency components, or,0 and oz,0, of the secular motion. Higher-order
Figure 6 The Mathieu stability diagram in (az,qz) space for the quadrupole ion trap in both the r and z directions. Regions of simultaneous overlap are labelled A and B.
(n) frequencies exist and the family of frequencies is described by or,n and oz,n as given by ou;n ¼ ðn þ bu =2ÞO;
0r no N
½8
No n o 0
½9
and ou;n ¼ ðn þ bu =2ÞO;
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Figure 9 Pure quadrupole field, or potential surface, for a quadrupole ion trap. Note the four poles of the surface and the similarity of the field shape to the trajectory in Figure 8. Figure 7 Stability diagram in (az,qz) space for the region of simultaneous stability in both r and z directions near the origin for the three-dimensional quadrupole ion trap; the iso-br and iso-bz lines are shown. The qz axis intersects the bz ¼ 1 boundary at qz ¼ 0.908, which corresponds to qmax in the mass-selective instability mode.
the ITSIM simulation program, while the potential surface was generated by calculating the potential for increments of 1 mm in both radial and axial directions.
Resonant Excitation
Figure 8 Trajectory of a trapped ion of m /z 105. The initial position was selected randomly from a population with an initial gaussian distribution (FWHM of 1 mm); qz ¼ 0.3; zero initial velocity. The projection onto the xy plane illustrates planar motion in three-dimensional space. The trajectory develops a shape that resembles a flattened boomerang. Reproduced from Nappi et al. (1997) International Journal of Mass Spectrometry and Ion Processes 161 : 77–85.
The simulated ion trajectory shown in Figure 8 resembles a roller-coaster ride and depicts the motion of an ion on the potential shown in Figure 9. The oscillatory motion of the ion results from the undulations of the potential surface, which can be envisaged as rotating. The simulation of the ion trajectory was carried out using
The motion of confined ions can be excited upon resonant irradiation at oz; resonant excitation is a powerful technique in ion trap mass spectrometry since predetermined waveforms composed of specified frequencies or frequency ranges can be used. Irradiation is effected by applying a supplementary potential of some hundreds of millivolts across the end-cap electrodes. Prior to resonant excitation, ions are focused collisionally to the ion trap centre by collisions with helium atoms. This process is described as ‘ion cooling’ in that ion kinetic energies are reduced to B0.1 eV, corresponding to B800 K. Resonant excitation, or ‘tickling’ of cooled ions, causes ions to move away from the ion trap centre so that they experience the trapping field and are accelerated to kinetic energies of tens of electronvolts. Resonant excitation is used to increase ion kinetic energy for the following purposes. (1) To eject unwanted ions during ionization and to isolate a narrow range of mass/charge ratios. (2) To promote endothermic ion/ molecule reactions. (3) To increase ion internal energy through momentum-exchange collisions with helium atoms; in the limit, ions dissociate. (4) To move ions towards an end-cap electrode where an image current can be detected for their nondestructive measurement and re-measurement. (5) To eject ions either for ion isolation or for mass-selective ejection while the applied frequency is swept. (6) To eject ions while the amplitude V of the main RF potential is ramped up; this mode, known as axial modulation, uses a fixed frequency to
Ion Trap Mass Spectrometers
eject ions just before their trajectories become unstable. In axial modulation, the resonant frequency is slightly less than half the main drive frequency O. Resonant excitation at lower frequencies has been used with great success to extend the normal mass range of the ion trap.
Operation of the Ion Trap as a Mass Spectrometer In the ion trap, gaseous molecules are bombarded with 50–80 eV electrons emitted from a heated filament and gated into the trap, as shown in Figure 10a. Under automatic gain control (AGC), the number of ions formed during 200–ms is used to scale the ionization time and produce the required number of ions. During ionization, an RF voltage V0 is applied to the ring electrode so as to confine ions in a given range of mass/charge ratio. Nascent ions are subjected to about 20 collisions per millisecond with helium at a pressure of 103 torr; those ions that are not ejected become focused near the trap centre. In Figure 10b, an RF amplitude is ramped over the period 30–85 ms, during which mass-selective ion ejection and mass analysis occur. Each ion species confined within the ion trap is associated with a qz value that lies on the qz axis on the stability diagram; ions of high mass/charge ratio have qz values near the origin, while ions of lower mass/charge ratio have qz values that extend towards the bz ¼ 1 stability boundary, as shown diagrammatically using stickpeople of various sizes in Figure 11a. At the intersection of the bz ¼ 1 stability boundary and the qz axis, where qz ¼ 0.908 (see Figure 7), the trajectories of trapped ions become unstable axially and ions leave the ion trap. Once the ion cloud has been focused collisionally to the ion trap centre, the amplitude of the RF potential is ramped; this operation, which is described as an analytical ramp
Figure 10 An overview of MS-in-time. (a) Step 1: a trapping RF amplitude is applied for 0–30 ms during which ions are formed from sample molecules and stored. (b) Step 2: an RF amplitude is ramped over the period 30–85 ms during which mass-selective ion ejection and mass analysis occurs.
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or analytical scan, increases the qz values of all ion species and, when qz ¼ 0.908 for each ion species, the ions are ejected axially through the end-cap electrodes. This mass-selective axial instability method of ion ejection has been supplanted by the use of axial modulation. Originally, axial modulation described resonant ejection of ions at a frequency of 485 kHz and at a qz value slightly less than 0.908. When the RF amplitude is ramped, ions come into resonance at 485 kHz as their qz values approach 0.908 and are ejected axially in order of increasing mass/charge ratio. Since ions are focused near the ion trap centre in the fashion of an onion, resonance ejection has the effect of removing the ions of low mass/ charge ratio residing in the innermost layer of the onion from the influence of space-charge perturbations induced by other ion species, so that ions are ejected free of spacecharge and with enhanced mass resolution. Resonant ejection, which can be carried out over a wide frequency range, is depicted pictorially in Figure 11b, which shows ions residing near the bottom of their respective axial
Figure 11 (a) Schematic representation of working points (that is, coordinates in az,qz space) in the stability diagram for several species of ions stored concurrently. The arrangement of working points with respect to mass/charge ratio is depicted by figures that differ in size. (b) Ions are shown residing near the bottom of ¯ z; the ladder their respective axial potential wells of depth D represents the opportunity for resonant ejection of an ion species.
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Ion Trap Mass Spectrometers
¯ z; the ladder represents resopotential wells of depth D nant ejection of an ion species. For axial modulation, the ladder is positioned at a qz value slightly less than 0.908. Resonantly ejected ions pass through holes in both endcap electrodes so that B50% impinge upon an electron multiplier located behind one of the end-cap electrodes; ion signals are created that produce a mass spectrum in order of increasing mass/charge ratio. A mass spectrum is obtained by running the scan function (see below) a number of times specified by the number of microscans; the signals from each microscan are averaged and yield a mass spectrum.
specificity. Under the influence of the tickle voltage, ions are moved from the centre to a region of higher potential, whereupon they are accelerated and their kinetic energies are increased. Subsequent collisions with helium atoms lead to enhancement of ion internal energy. In analytical applications, where the objective is to dissociate all isolated ions and to maximize the trapping of fragment ions produced, ion kinetic energy uptake must be balanced with incremental accumulation of internal energy so that ejection of isolated ions and fragment ions is avoided.
Tandem Mass Spectrometry Scan Function The above operation can be expressed succinctly in a scan function, which shows the temporal variation of the potentials applied to the electrodes such that a scan function is a visual representation of the sequence of program segments in the software that controls ion trap operation. The scan function for the above mass spectrometric operation is shown in Figure 12.
Collision-Induced Dissociation Collision-induced dissociation (CID) of an isolated ion species in a quadrupole ion trap is a powerful technique for both the determination of ion structures and the analytical identification of compounds with high
Tandem (Latin: ‘‘at length’’) mass spectrometry, MS/MS, is the practice of performing one mass-selective operation after another, much as the riders are seated on a tandem bicycle. The first mass-selective operation isolates an ion species designated as the parent ion, while the second determines the mass/charge ratios of the fragment, or product, ions formed by CID of the parent ions. MS/MS with a quadrupole ion trap, where successive mass-selective operations are carried out in time, offers a number of advantages. First, since the ion trap operates in a pulsed mode, mass-selected ions can be accumulated over time. Second, since CID is wrought by many collisions of mass-selected ions with helium atoms wherein the energy transferred per collision is small, dissociation channels of lowest activation energy are accessed almost exclusively. Third, all isolated ions can be dissociated and fragment ions arising from some 90% of them can be confined. Fourth, a sequence of several mass-selective operations can be performed as in MSn. When gas chromatography is interfaced with an ion trap tandem mass spectrometer, individual compounds can be detected at the hundreds of femtograms level. The high specificity or informing power obtainable with GCMS/MS is achieved by observation of specific fragment ion signals from an isolated molecular ion species Mdþ formed from M that elutes within a specified retentiontime window.
Chemical Ionization and Ion Molecule Reactions
Figure 12 Scan function for obtaining an EI mass spectrum. The scan function shows the ionization period, A, followed immediately by the analytical ramp with concurrent axial modulation. Note that the pre-scan for the automatic gain control algorithm is not shown.
In the quadrupole ion trap, several types of reactions can and do occur simultaneously and spontaneously once electron ionization of a compound has occurred. Ion– molecule reactions involving charge transfer, proton transfer and clustering occur sequentially, resulting in the formation of stable even-electron ions. Proton transfer chemical ionization (CI) involves the transfer to a neutral species of a proton (or other even-electron charged particles) from an ion that has been formed in an
Ion Trap Mass Spectrometers
ion–molecule reaction. Common CI reagents are CH5þ and C2H5þ, which are formed rapidly and can be isolated prior to reaction. CI reagent ions can be created externally and injected into the ion trap, isolated massselectively and allowed to react with sample molecules.
Conclusions Ion trap mass spectrometry is a versatile technique of high sensitivity and high specificity. The relatively low cost of commercial instrumentation has permitted a substantial growth in the practice of mass spectrometry. The theory of ion trap operation differs from those of other mass spectrometers and presents an exciting challenge to the mass spectrometry community. See also: Biological Applications of IR, Chemical Ionization in Mass Spectrometry, Chromatography-MS, Methods, Electrospray Ionization in Mass Spectrometry, Fourier-Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICR MS), Ion Molecule Reactions in Mass Spectrometry, Ion Structures in Mass Spectrometry, Mass Spectrometry, Historical Perspective, MS Based Metabonomics, MS–MS and MSn, Proteomics, Proton Affinities Determined Using Mass Spectrometry, Quadrupoles, Use of in Mass Spectrometry
Further Reading Cooks RG and Kaiser RE Jr (1990) Quadrupole ion trap mass spectrometry. Accounts of Chemical Research 23: 213--224. Dawson PH (1976) Quadrupole Mass Spectrometry and Its Applications. Amsterdam: Elsevier. Dawson PH and Whetten NR (1969) Radiofrequency quadrupole mass spectroscopy. Electronics and Electron Physics 27: 58--158. Fischer E (1959) Three-dimensional stabilization of charge carriers in a quadrupole field. Zeitschrift fu¨r Physik 156: 1--26. Glish GL and McLuckey SA (eds.) (1991) Quadrupole Ion Traps ( International Journal of Mass Spectrometry and Ion Processes 106).
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Hardman M and Makarov A (2003) Interfacing the Orbitrap mass analyzer to an electrospray ion source. Analytical Chemistry 75: 1699–1705. Hu O, Noll RJ, Li H, Makarov A, Hardman M, and Cooks RG (2005) The Orbitrap: A new mass spectrometer. Journal of Mass Spectrometry 40: 430–443. Makarov A (2000) Electrostatic axially harmonic orbital trapping: A highperformance technique of mass analysis. Analytical Chemistry 72: 1156–1162. March RE (1992) Ion trap mass spectrometry. International Journal of Mass Spectrometry and Ion Processes 118/119: 71. March RE (1997) An introduction to quadrupole ion trap mass spectrometry. Journal of Mass Spectrometry 32: 351. March RE, Hughes RJ, and Todd JFJ (1989) Quadrupole Storage Mass Spectrometry. New York: Wiley Interscience. March RE and Todd JFJ (eds.) (1995) Practical Aspects of Ion Trap Mass Spectrometry, Modern Mass Spectrometry Series; vol. 1, Fundamentals, ISBN 0-8493-4452-2; vol. 2, Instrumentation, ISBN 0-8493-8253-X; vol. 3, Chemical, Biomedical, and Environmental Applications, ISBN 0-8493-8251-3. Boca Raton, FL: CRC Press. Mathieu E (1868) Journal de Mattematiques Pures et Applies (J. Liouville) 13: 137. (See also McLachan NW (1947) Theory and Applications of Mathieu Functions. Oxford: Clarendon Press and Campbell R (1955) The´orie Ge´ne´rale de l’Equation de Mathieu. Paris: Masson. Nappi M, Weil C, Cleven CD, Horn LA, Wollnik H, and Cooks RG (1997) Visual representations of simulated three-dimensional ion trajectories in an ion trap mass spectrometer. International Journal of Mass Spectrometry and Ion Processes 161: 77--85. Nourse BD and Cooks RG (1990) Aspects of recent developments in ion trap mass spectrometry. Analytica Chimica Acta 228: 1--11. Paul W (1990) Electromagnetic traps for charged and neutral particles (Nobel Lecture). Angewandte Chemie 29: 739--748. Paul W and Steinwedel H (1960) Apparatus for separating charged particles of different specific charges. German Patent 944 900, 1056; US Patent 2 939 952. Reiser HP, Kaiser RE Jr, and Cooks RG (1992) A versatile method of simulation of the operating of ion trap mass spectrometers. International Journal of Mass Spectrometry and Ion Processes 121: 49--63. Schwartz JC, Senko MW, and Syka JEP (2002) A two-dimensional quadrupole ion trap mass spectrometer. Journal of the American Society for Mass Spectrometry 13: 659--669. Stafford GC Jr, Kelley PE, Syka JEP, Reynolds WE, and Todd JFJ (1984) Recent improvements in and analytical applications of advanced ion trap technology. International Journal of Mass Spectrometry and Ion Processes 60: 85--98. Todd JFC (1991) Mass Spectrometry Reviews 10: 3. Wuerker RF, Shelton H, and Langmuir RV (1959) Journal of Applied Physics 30: 324.