TOF mass spectrometer operated in negative mode

Abstract

In one aspect, a time-of-flight (TOF) mass analyzer is disclosed, which includes an input for receiving a plurality of ions (herein also referred to as "primary ions"), an ion acceleration region through which the received ions are accelerated, a push electrode for directing the received ions into the ion acceleration region, and a field-free ion drift region for receiving said accelerated ions, said field-free ion drift region having an ion detector positioned at a distal end thereof. At least one magnet is positioned relative to the electric field-free region so as to establish a magnetic field in at least a portion of the electric field-free region for deflecting electrons entering the electric field-free region so as to inhibit the electrons from reaching the ion detector.

Description

TOF MASS SPECTROMETER OPERATED IN NEGATIVE MODERelated Applications

[0001] This application claims priority to U.S. provisional application no. 63 / 608,438 filed on December 11, 2023, entitled “TOF Mass Spectrometer Operated in Negative Mode,” which is incorporated herein by reference in its entirety.Technical Field

[0002] The present disclosure relates generally to systems and methods for performing mass spectrometry, and more particularly to such systems and methods that utilize time-of-flight (ToF) mass analyzers.Background

[0003] The present disclosure provides systems and methods for performing mass spectrometry, and particularly such systems and methods that allow achieving higher sensitivity, and throughput in mass spectrometers utilizing time-of-flight (TOF) mass analyzers.

[0004] Mass spectrometry (MS) is an analytical technique for determining the structure of test chemical substances with both qualitative and quantitative applications. MS can be useful for identifying unknown compounds, determining the composition of atomic elements in a molecule, determining the structure of a compound by observing its fragmentation, and quantifying the amount of a particular chemical compound in a mixed sample. Mass spectrometers detect chemical entities as ions such that a conversion of the analytes to charged ions must occur.

[0005] Time-of-flight mass spectrometry relies on different arrival times to separate ions having different m / z ratios. In such systems, the mass analyzer accelerates ions via their passage through a region in which an electric field imparts kinetic energy to the ions. The accelerated ions enter a field-free ion drift region in which they travel to reach an ion detector that detects the ions. The time required for the ions to pass through the drift region to reach the ion detector depends on their m / z ratios, thereby allowing the ions to be separated based on their m / z ratios.

[0006] In some applications, and particularly in analysis of negatively- charged ions, the transit of the ions through a TOF mass analyzer may result in generation of electrons. Suchelectrons can find their way to the ion detector of the TOF mass analyzer and produce noise in the ion detection data, e.g., in the form of a continuous bump in the resultant mass spectra.Summary

[0007] In one aspect, a time-of-flight (TOF) mass analyzer is disclosed, which includes an input for receiving a plurality of ions (herein also referred to as “primary ions”), an ion acceleration region through which the received ions are accelerated, a push electrode for directing the received ions into the ion acceleration region, and an electric field-free ion drift region for receiving the accelerated ions. An ion detector is positioned at a distal end of the field-free ion drift region. At least one magnet is positioned relative to the electric field-free region so as to establish a magnetic field in at least a portion of the electric field-free region for deflecting electrons entering the electric field-free region so as to inhibit the electrons from reaching the ion detector. In various embodiments, the magnet can be a permanent magnet. In other embodiments, an electromagnet, or a combination of a permanent magnet and an electromagnet can be utilized.

[0008] In some embodiments, the plurality of ions includes negatively- charged ions. The negatively- charged ions can be singly or multiply charged.

[0009] In some embodiments, the ion acceleration region extends from the push electrode to a first mesh electrode (herein also referred to as a “grid electrode”). By way of example, the application of a voltage difference between the push electrode and a DC bias voltage applied to the field free region, e.g., an electrode of the ion acceleration region, can generate an electric field for accelerating ions received by the mass analyzer to a target energy, e.g., to an energy in a range of about 5 keV to about 20 keV, by way of example.

[0010] In some embodiments, a first ion mirror is positioned downstream of the ion acceleration region and is separated from the ion acceleration region via a portion of the field- free region. In some such embodiments, the first ion mirror can include at least a second mesh electrode. Without being limited to any particular theory, in some cases, the collision of negatively- charged ions accelerated through the ion acceleration region of the TOF mass analyzer with the one or more mesh electrodes of the ion mirror can generate secondary positive ions or electrons. The impact of such secondary positive ions with a mirror plate of the ionmirror can in turn generate electrons, which are accelerated via the potential difference between the mirror plate and the one or more mesh electrodes and directed towards the ion detector.

[0011] In some embodiments, the magnet can generate a magnetic field with a magnitude in a range of about 0.5 mT to about 100 mT in said portion of the electric field-free region. By way of example, in some embodiments, the magnitude of such a magnetic field can be in a range of about 1 mT to about 10 mT, or in a range of about 10 mT to about 20 mT, or in a range of about 20 mT to about 30 mT, or in a range of about 30 mT to about 40 mT, or in a range of about 40 mT to about 50 mT, or in a range of about 50 mT to about 60 mT, or in a range of about 60 mT to about 70 mT, or in a range of about 70 mT to about 80 mT, or in a range of about 80 mT to about 90 mT, or in a range of about 90 mT to about 100 mT.

[0012] In general, the direction of the magnetic field is not parallel to the general direction of the propagation of the ions though the electric field-free region. For example, in various embodiments, the direction of the magnetic field is not parallel to a longitudinal axis of the electric field- free region, but rather makes a non-zero angle therewith. For example, in many embodiments, the direction of the magnetic field is orthogonal to a general propagation direction of ions through the magnetic field region so as to optimize the magnitude of the force applied to the electrons, thereby facilitating the redirection of the electrons and hence prevent their arrival at the downstream ion detector.

[0013] The TOF mass analyzer can include a housing (herein also referred to as a “liner”) that provides an enclosure (herein also referred to as a chamber) in which various components of the TOF mass analyzer are positioned. In some embodiments, the magnet can be positioned external to the chamber. In other embodiments, the magnet can be positioned within the chamber.

[0014] The position of the magnet relative to the ion detector can vary in different embodiments and can be selected based on the present teachings to provide sufficient deflection of the electrons to reduce, and preferably eliminate, the generation of noise artifacts due to the electrons in the resultant mass spectra. For example, in some embodiments, a linear separation between the center of the magnet and the ion detector may be more than 2 / 3 of the linear distance between the last ion mirror and the downstream ion detector.

[0015] In some embodiments, more than one magnet may be employed for changing the propagation direction of the electrons so as to inhibit their arrival at the ion detector. For example, at least two magnets that are axially and / or radially separated from one another may be employed. In such embodiments, the magnitude of a magnetic field generated by the magnets can be the same or different. In some embodiments, a plurality of magnets may be positioned relative to one another to generate a magnetic field gradient along the portion of the electric field (free) region to which the magnetic field is applied. By way of example, such a magnetic field gradient may provide a magnetic field with a decreasing magnitude from the last ion mirror to the ion detector.

[0016] In a related aspect, a method of operating a time of flight (TOF) mass analyzer is disclosed, which includes introducing a plurality of ions (herein also referred to as “primary ions”) into a time-of-flight (TOF) mass analyzer, accelerating the ions in an ion acceleration region to generate accelerated ions, introducing the accelerated ions into an electric field-free ion drift region at a proximal end thereof to be incident on an ion detector positioned at a distal end of the electric field-free ion drift region, and applying a magnetic field to at least a portion of the electric field-free ion drift region for deflecting electrons entering the electric field-free ion drift region so as to inhibit the electrons from reaching the ion detector.

[0017] In some embodiments, the ions can be negatively-charged ions, including singly or multiply charged ions.

[0018] In general, the magnetic field includes at least one field component that has a direction that is orthogonal to a general direction of the propagation of ions through the magnetic field.

[0019] In some embodiments, the magnitude of the magnetic field (or at least its component that is orthogonal to the general propagation direction of the ions through the magnetic field region) can be in a range of about 0.5 mT to about 100 mT, or in any subrange within this range, such as in a range of about 1 mT to about 10 mT, or in a range of about 10 mT to about 20 mT, or in a range of about 20 mT to about 30 mT, or in a range of about 30 mT to about 40 mT, or in a range of about 40 mT to about 50 mT, or in a range of about 50 mT to about 60 mT, or in arange of about 60 mT to about 70 mT, or in a range of about 70 mT to about 80 mT, or in a range of about 80 mT to about 90 mT, or in a range of about 90 mT to about 100 mT.

[0020] In some embodiments, the magnetic field can be substantially uniform over said at least a portion of the electric field-free region. Alternatively, the magnetic field can be non- uniform (e.g., it can exhibit a non-uniform magnitude) over said at least a portion of the electric field-free region. By way of example, and without limitation, the varying magnetic field can be characterized by a magnetic field gradient exhibiting a decreasing magnitude from the proximal end of the electric field-free region to the ion detector.

[0021] As noted above, while in some embodiments the magnetic field can be generated by one or more magnets that are positioned external to the electric field-free region, in other embodiments the magnetic field can be generated by one or more magnets that are positioned within the electric field-free region.

[0022] Further understanding of various aspects of the present teachings can be obtained with reference to the following description in conjunction with the associated drawings, which are described briefly below.Brief Description of the Drawings

[0023] FIG. 1 is a flow chart depicting various steps of a method for operating a TOF mass analyzer in accordance with an embodiment of the present teachings,

[0024] FIG. 2A is a schematic side view of a TOF mass analyzer according to an embodiment of the present teachings,

[0025] FIG. 2B depicts an axial view of a portion of the field-free region of the TOF mass analyzer depicted in FIG. 2A, illustrating several magnetic field lines associated with a magnet positioned external to a field-free region of the TOF mass analyzer,

[0026] FIG. 3A is a side schematic view of a TOF mass analyzer according to an embodiment in which three magnets are employed for deflecting electrons so as to inhibit their arrival at a downstream ion detector of the TOF mass analyzer,

[0027] FIG. 3B illustrates a hypothetical magnetic field gradient that can be established in a portion of a field-free region of a TOF mass analyzer in accordance with an embodiment of the present teachings,

[0028] FIG. 3C is a side schematic view of a TOF mass analyzer according to an embodiment, which includes a magnet positioned within the chamber of the TOF mass analyzer,

[0029] FIG. 3D is a side schematic view of a TOF mass analyzer according to another embodiment in which two radially separated magnets are employed for deflecting electrons so as to inhibit their arrival at a downstream ion detector,

[0030] FIG. 4A is a schematic side view of an ion mirror as well as the path of negative ions through the ion mirror and the production of secondary positive ions via impact of primary ions with mesh electrodes of the ion mirror, where the secondary positive ions cause the production of electrons from the mirror plate of the ion mirror,

[0031] FIG. 4B shows background noise measured using a TOF mass analyzer having two ion mirrors, such as that shown in FIG. 2A, as well as the timings associated with passage of ions through various components of the ion mirrors, where secondary particles are produced,

[0032] FIG. 5A shows a mass spectrum of product ions associated with a precursor ion acquired using a TOF mass analyzer without application of a magnetic field to the field-free region of the mass analyzer,

[0033] FIG. 5B shows a mass spectrum of the same product ions as that in FIG. 5A acquired using the same TOF mass analyzer but with application of an 8 mT magnetic field to the field- free region of the mass analyzer,

[0034] FIG. 6 schematically depicts a TOF mass analyzer having an ion detector with four ion detection channels, which were employed to generate the data shown in FIGS. 6A - 6X,

[0035] FIGS. 6A - 6X present mass spectra of product ions associated with a precursor ion having an m / z=-792 (clusters of sodiated trifluoroacetic acid: CnHOnFisNas) and its CID products without and with application of a magnetic field at different magnetic field strengths,

[0036] FIG. 7 shows calculated trajectories of electrons with an energy of 8 keV during their transit from the second ion mirror of the TOF mass analyzer depicted in FIG. 2 to its ion detector under different magnetic field conditions,

[0037] FIG. 8A illustrates an electron noise bump spectrum obtained using a TOF mass analyzer similar to that shown in FIG. 2A, where the ions were sodiated trifluoroacetic acid, and

[0038] FIG. 8B shows normalized “bump” intensities for each of the regions shown in the spectrum illustrated in FIG. 8A.Detailed Description

[0039] It will be appreciated that for clarity, the following discussion will explicate various aspects of embodiments of the applicant’s teachings, while omitting certain specific details wherever convenient or appropriate to do so. For example, discussion of like or analogous features in alternative embodiments may be somewhat abbreviated. Well-known ideas or concepts may also, for brevity, not be discussed in any great detail. The skilled person will recognize that some embodiments of the applicant’s teachings may not require certain of the specifically described details in every implementation, which are set forth herein only to provide a thorough understanding of the embodiments. Similarly, it will be apparent that the described embodiments may be susceptible to alteration or variation according to common general knowledge without departing from the scope of the disclosure. The following detailed description of embodiments is not to be regarded as limiting the scope of the applicant’s teachings in any manner.

[0040] As used herein, the terms "about" and "substantially equal" refer to variations in a numerical quantity that can occur, for example, through measuring or handling procedures in the real world; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of compositions or reagents; and the like. Typically, the terms "about" and "substantially" as used herein means 10% greater or less than the value or range of values stated or the complete condition or state. For instance, a concentration value of about 30% or substantially equal to 30% can mean a concentration between 27% and 33%. The terms also refer to variations that would be recognized by one skilled in the art as being equivalent so long as such variations do not encompass known values practiced by the prior art.

[0041] As used herein the term "and / or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as

[0042] Various terms are used herein according to their ordinary meanings in the art. The terms “electric field-free region” and “electric field-free ion drift region” and “field-free region” and “field-free ion drift region” are used interchangeably to refer to a region of the TOF mass analyzer in which no electric field is present or any electric field that may be present is not sufficiently strong to cause any substantial change in the trajectory of ions passing through the field-free region. By way of example, any electric field that may be present in the field-free region would have a magnitude less than about 1 OV / mm. As discussed herein, in various embodiments, a magnetic field may be applied to the electric field-free region to cause deflection of electrons present in this region from their original propagation path so as to inhibit their arrival at a downstream ion detector.

[0043] The terms “mesh electrode” and “grid electrode” are used herein interchangeably to refer to a conductive electrode having openings through which ions can pass.

[0044] When a TOF mass analyzer is employed to analyze negatively- charged ions, the ions passing through the mass analyzer can collide with one or more mesh electrodes. In some cases, such collisions result in production of high energy electrons. Alternatively, or in addition, the collision of ions entering the mass analyzer with the mesh electrodes can result in the generation of secondary ions (typically lighter ions), which may in turn collide with one or more mesh electrodes or the plate electrodes of the mass analyzer to generate electrons (e.g., cause ejection of electrons from a metal electrode). At least a portion of such electrons can find their way to an ion detector, where they lead to the generation of noise in the mass spectral data.

[0045] By way of example, as seen in FIG. 5A, in some cases, the background noise generated by the electrons striking the ion detector can appear as a continuous bump in a mass spectrum. Such a bump in a mass spectrum can render identification of certain mass signals difficult or even impractical. In particular, in mass spectra acquired via electron activated dissociation (EAD), the mass signals associated with product ions can be very weak. In such cases, the noise artifacts, such as the bump illustrated in the mass spectrum of FIG. 5A, can interfere with the identification of such weak fragment signals.

[0046] As discussed in more detail below, in various embodiments, a magnetic field is established in at least a portion of a field-free ion drift region of a TOF mass analyzer to deflect electrons entering that region so as to inhibit the electrons from striking an ion detector of the mass analyzer. Such deflection of the electrons can reduce, and preferably eliminate, noise that could otherwise be generated due to the electrons striking the ion detector.

[0047] FIG. 1 is a flow chart depicting various steps of an embodiment of a method according to the present teachings for operating a time-of-flight (TOF) mass analyzer in which a plurality of ions (herein also referred to as “primary ions”) is introduced into the mass analyzer and the ions are accelerated to generate a plurality of accelerated ions. By way of example, and without limitation, the ions can be accelerated to an energy in a range of about 5 keV to about 20 keV. The accelerated ions are introduced into an electric field-free ion drift region at a proximal end of the drift region such that the accelerated ions can travel through the electric field-free region to be received by an ion detector that is positioned at a distal end of the electric field-free region. A magnetic field can be applied to at least a portion of the electric field-free region to deflect electrons, if any, entering the electric field-free region so as to inhibit the electrons from reaching the ion detector.

[0048] In some embodiments, the magnetic field can be present within the entire volume of the electric field-free region. In other embodiments, the magnetic field can be present within only a fraction of the electric field-free region. By way of example, the magnetic field can be present within a portion of the field-free region that extends from a proximal end of that region, e.g., the end at which a last ion mirror of the TOF mass analyzer is positioned, to a boundary between the last ion mirror and the ion detector. In other words, the portion of the field-free region from the boundary to the ion detector can be substantially free of not only any electric field, but also any magnetic field.

[0049] In general, the magnetic field does not exhibit a sharp transition between two portions of the electric field-free regions in only one of which the magnetic field is intended to be established. In some cases, the transition of the magnetic field between such two portions of the electric field- free regions can be characterized by a gradient, e.g., a linear gradient. Further, in some embodiments, the magnetic field can be substantially uniform within at least a fraction of a portion of the field- free region to which the magnetic field is applied.

[0050] In various embodiments, the magnetic field has at least one component that is orthogonal to a general axial direction along which the ions propagate through the electric field- free region (e.g., along the longitudinal axis of the field-free region or along a direction that forms an angle with the longitudinal axis). The magnitude of the magnetic field can be selected based on a particular application to cause sufficient deflection of the electrons so as to prevent the electrons, or at least a large fraction of the electrons, from striking the ion detector. By way of example and without limitation, the magnitude of the magnetic field can be in a range of about 0.5 mT to about 100 mT, or within any subrange of this range.

[0051] In various embodiments, the primary ions are negatively-charged ions. By way of example, and without limitation, such negatively-charged ions can be singly or multiply charged.

[0052] A method according to various embodiments of the present teachings can be implemented in a variety of different types of TOF mass analyzers, in particular TOF mass analyzers that include ion mirrors.

[0053] For example, FIG. 2A schematically depicts a TOF mass analyzer 100 according to an embodiment, which includes a housing 101 (herein also referred to as a “liner”) that encloses an evacuated enclosure (herein also referred to as a chamber) 101a in which various components of the TOF mass analyzer are disposed. The chamber can be characterized by a longitudinal axis (LA) that extends between a proximal end and a distal end of the chamber 101a and an orthogonal radial (transverse) axis (TA).

[0054] The TOF mass analyzer includes an inlet 102 for receiving a plurality of ions and a push electrode 104 for directing the received ions into an ion acceleration region 106 of the mass analyzer in which the ions can experience an electric field that can cause their acceleration. For example, a plurality of voltage pulses can be applied to the push electrode to direct the ions arriving at the push electrode into the ion acceleration region. The ion acceleration region 106 can include a plurality of electrodes maintained at uniform-gradient (or slope) electric potentials to generate an electric field for causing the acceleration of the ions. By way of example, and without limitation, the ions can be accelerated to a kinetic energy in a range of about 5 keV to about 20 keV.

[0055] The accelerated ions travel through a field-free ion drift region 108 of the mass analyzer to reach a first ion mirror 110, which includes a plurality of mesh electrodes 110a and a mirror plate electrode 110b maintained at appropriate electric potentials in a manner known in the art to slow down the received ions and cause the received ions to reverse their propagation direction to propagate to a second ion mirror 112. Similar to the first ion mirror 110, the second ion mirror 112, which includes a plurality of mesh electrodes 112a and a mirror plate electrode 112b, also causes a reversal in the propagation direction of the ions to direct the ions to an ion detector 114 that is positioned at a distal end of the field-free ion drift region of the TOF mass analyzer. The ion detector can generate ion detection signals in response to the incidence of the ions thereon, where the ion detection signals can be processed by an analysis module (not shown) to generate a mass spectrum of the ions incident on the ion detector.

[0056] With continued reference to FIG. 2A, in this embodiment, a magnet 116, in the form of a permanent magnet, is positioned external to the chamber 101, i.e., external to the field-free region, of the TOF mass analyzer to generate a magnetic field within at least a portion of the field-free ion drift region upstream of the ion detector.

[0057] By way of illustration, FIG. 2B shows an example of magnetic field lines generated by the magnet 116 within a portion of the field-free ion drift region. An electron passing through the magnetic field can experience a force (generally referred to as the Lorentz force), which is proportional to the product of the electron charge and the vector cross product of the electron velocity and the applied magnetic field, as provided by the following relation:F oc q VxB Eq. (1) wherein,F denotes a force vector applied to an electron, q denotes the electric charge of the electron, V denotes the velocity vector associated with the electron, B denotes the magnetic field vector, and x denotes a cross product of the force and the magnetic field vectors.

[0058] The magnetic field lines have components that are not parallel to the propagation direction of the electrons to ensure that a deflection force would be applied to the electrons passing through the magnetic field. As seen from the above Eq. (1), the Lorentz force generated by the magnetic field on the electrons is in a direction perpendicular to the direction of the electron’s motion, and hence deflects the electron from its initial propagation path. In other words, the force exerted on an electron via its passage through the magnetic field will cause the electron to deviate from its initial propagation path and hence prevent the electron from reaching the downstream ion detector.

[0059] While in the above embodiment a single magnet is employed for deflecting the electrons, in other embodiments two or more magnets may be used for causing the deflection of the electrons passing through the field- free ion drift region of the TOF mass analyzer. By way of example, FIG. 3A schematically depicts an example of such a TOF mass analyzer 200, which has a structure similar to that of TOF mass analyzer 100 discussed above, with an ion acceleration stage 202, two ion mirrors 204 / 206 and an ion detector 208 disposed within an evacuated chamber 210.

[0060] While the above TOF mass analyzer 100 includes a single magnet for deflecting the electrons generated in the TOF mass analyzer, TOF mass analyzer 200 includes three magnets 212a, 212b, and 212c (herein collectively referred to as magnets 212) that are positioned external to the mass analyzer’s evacuated chamber. The magnetic fields generated by these magnets superimpose within a portion of the field-free ion drift region to generate a resultant magnetic field, which can cause the deflection of electrons passing through the field-free region. In some embodiments, the magnitude of a magnetic field generated by each of the magnets is substantially similar to the respective magnitude of a magnetic field generated by any of the other magnets. In other embodiments, the strengths of the magnetic fields generated by two or more of the magnets can be different.

[0061] In some embodiments, the resultant magnetic field generated by a plurality of magnets can provide a magnetic field gradient that extends, e.g., from the second ion mirror to the ion detector. By way of illustration, FIG. 3B schematically depicts a hypothetical example of such a magnetic field gradient that decreases substantially linearly from the second ion mirror to the ion detector in an example of implementation of a TOF mass analyzer according to thepresent teachings. In other embodiments, the magnetic field gradient may have a non-linear profile.

[0062] By way of additional examples, FIG. 3C schematically depicts a TOF mass analyzer 300 according to another embodiment, which is similar to the TOF mass analyzer 100 discussed above except that in the mass analyzer 300, a magnet 310 for deflecting electrons to inhibit their arrival at the ion detector of the mass analyzer is positioned within, rather than external to, the chamber of the mass analyzer. Specifically, the TOF mass analyzer 300 includes a housing 302, which surrounds an enclosure (vacuum chamber) in which an ion acceleration region 304, two ion mirrors 306a / 306b and an ion detector 308 are disposed. A magnetic field generated by magnet 310 can cause the deflection of electrons from a path that would have led to the ion detector 308.

[0063] Further, FIG. 3D shows a TOF mass analyzer 314 according to another embodiment, which includes two magnets 316a / 316b that are radially separated from one another, i.e., in a direction orthogonal to the longitudinal axis of the chamber of the mass analyzer. In various embodiments, the magnetization directions of the two magnets are parallel. The other components of the TOF mass analyzer 314 and their arrangements are the same as those in the mass analyzer 300. While in this embodiment both magnets 316a / 316b are positioned external to the mass analyzer’s chamber, in other embodiments one or both of these magnets 316a / 316b can be positioned within the chamber.

[0064] Electrons can be generated via different mechanisms as the ions pass through the TOF mass analyzer. For example, as noted above, in some embodiments the impact of ions entering the mass analyzer with one or more mesh electrodes of an ion mirror can generate secondary positive ions, which can in turn cause the ejection of electrons from a mirror plate of the ion mirror.

[0065] The following examples are provided for further elucidation of various aspects of the present teachings and not to provide necessarily optimal ways of practicing the present teachings and / or optimal results that can be achieved.

[0066] Examples

[0067] Example 1

[0068] Without being limited to any particular theory, it is believed that at least a portion of electrons finding their way to a TOF mass analyzer’s ion detector are generated via the following process: (1) the collision of primary negative ions with grid electrode(s) of an ion mirror of the TOF mass analyzer generates secondary positive ions, (2) the positive ions are accelerated toward the mirror plate and (4) the impact of the positive ions with the mirror plate generates electrons, (3) the generated electrons are accelerated in the direction of the ion detector.

[0069] By way of illustration, FIG. 4A shows the entry of primary ions into an ion mirror 400 having two grid electrodes 402a / 402b and a mirror plate 402c. In this example, the grid electrodes 402a and 402b are held at the ground and +6 kV electric potentials, respectively. Subsequent to the passage of the negative ions through the grid electrode 402a, the ions are slowed down and finally reflected back at the ion mirror plate and accelerated out of the ion mirror. A portion of the negatively- charged ions hit the conductive material of the grid electrodes 402a and / or 402b to generate a plurality of secondary positive ions. The secondary positive ions are accelerated towards the ion mirror plate and cause the ejection of electrons from the plate.

[0070] The electrons are in turn accelerated by the electric field established due to the electric potentials between the ion mirror plate and the grid electrodes and the accelerated electrons travel in the direction of the downstream ion detector. As in this example, the potential difference between the mirror plate and the grid electrode 402a is 8 kV, the accelerated electrons will have an energy of 8 keV as they exit the ion mirror.

[0071] Alternatively, a portion of the negatively-charged ions hit the conductive material of the grid electrodes 402b to generate a plurality of secondary electrons directly, without an intermediate stage of producing positive ions. The potential difference between the mirror grid electrodes 402a and 402b is 6 kV, the accelerated electrons will have an energy of 6 keV as they exit the ion mirror.

[0072] The ion detection data presented in FIG. 4B corroborates the model for the generation of electrons discussed above in connection with FIG. 4A. FIG. 4B shows thatbackground noise spectrum generated by the ion detector, illustrating at least four peak profiles. FIG. 4B also shows, via a plurality of arrows, the times at which ions would be passing through the mesh electrodes of the two ion mirrors, namely, 37.1 ps, 39.6 ps, 43.6 ps, and 46.1 ps (indicated as “a”, “b”, “c”, “d”, “e”, and “d” in the inset of FIG. 4B). The dark trace in FIG. 4B was recorded without the use of magnets while the gray trace was recorded using a magnet and does not show any electron noise bumps.

[0073] The positions of the arrows, which indicate the timings associated with the passage of ions, and the peak profiles in the background noise spectrum are roughly matched. As electrons are very light particles, their travel time from the second mirror to the ion detector is negligibly small (it is essentially instantaneous in the context of a typical TOF time scale).

[0074] Thus, this data corroborates the mechanism proposed herein by which electrons are generated.

[0075] Example 2

[0076] Mass spectra of a sample containing phospholipids 18:1 (9Z) / 18: 1 (9Z) / PG at a concentration of 100 ng / mL was obtained using a Sciex Zeno TOF 7600 mass spectrometer, which was modified to include a magnet positioned external to the field-free chamber for establishing a magnetic field within the field-free region. The mass spectrometer included a TOF mass analyzer with two ion mirrors in a manner similar to the TOF mass analyzer depicted in FIG. 2A. The phospholipids were ionized (or deprotonated), and negative precursors were generated by electrospray ionization. The isolated precursor ions at an energy of 35 eV were subjected to electron activated dissociation using an electron beam at an intensity of 3.5 pA to generate a plurality of product ions.

[0077] The product ions were trapped in an ion trap using a conventional trapping mode with the following parameters: ion loading time = 50 ms, reaction time = 20 ms and extraction time = 1ms. Subsequently, the trapped product ions were released to be received by a downstream TOF mass analyzer.

[0078] Two sets of mass spectra of the product ions were acquired: (a) without the application of a magnetic field to the field-free region, and (b) with the application of a magnetic field to the field- free region. Whereas the mass spectrum acquired without the magnetic fieldexhibited noise artifacts caused by the impact of electrons on the mass analyzer’s ion detector, the respective mass spectrum acquired while applying an 8 mT magnetic field to the field-free region of the mass analyzer did not show such noise artifacts.

[0079] Specifically, FIG. 5A shows the mass spectrum of the product ions without the use of a magnetic field for deflecting electrons so as to inhibit the electrons from striking the ion detector. This spectrum exhibits a “noise bump” due to the noise generated by the electrons, which renders identification of weak mass signals difficult.

[0080] In contrast, FIG. 5B shows the mass spectrum of the same product ions when a magnetic field having a magnitude of 8 mT was applied along the ion path in the field-free region. The spectrum depicted in FIG. 5B shows that the use of the magnetic field has resulted in the elimination of the “noise bump” observed in the spectrum of FIG. 5A.

[0081] Example 3

[0082] The data presented in this example was also acquired using the modified Sciex Zeno TOF 7600 system that was modified by addition of a magnet to allow the application of a magnetic field to the field-free region of its TOF mass analyzer. The sample was clusters of sodiated trifluoroacetic acid: CnHOnFisNas, which produced a precursor with m / z = -792 by electrospray ionization with a negative charge.

[0083] Because the cluster was fragile, fragments produced by collisional activation in the Q2 were also observed (periodic peaks in FIGS. 6A - 6X). The precursor ions were isolated using a quadrupole mass filter and transferred to the TOF analyzer via Q2 collision cell. The product ions were trapped in an ion trap and then subsequently released to reach a TOF mass analyzer.

[0084] As illustrated schematically in FIG. 6, the ion detector of the TOF mass analyzer included four ion channels, herein referred to as MPC chi, MPC ch2, MPC ch3, and MPC ch4. The set of MCP channels works as a positional detector of electron arrival.

[0085] FIGS. 6A, 6B, 6C, and 6D show the mass spectra of the product ions that were obtained without using a magnet and by analyzing the ion detection data generated in the four channels of the ion detector. The “noise bump” due to the electrons striking the ion detector isvisible in these spectra. The bump was the strongest at MCP chi (as shown in FIG. 6). This indicates that the electrons are flying “upright” from the 2ndmirror to the detector.

[0086] FIGS. 6E, 6F, 6G, and 6H in turn show the respective spectra of the product ions acquired while applying a magnetic field of 0.06 mT to the field-free ion drift region of the TOF mass analyzer.

[0087] FIGS. 61, 6J, 6K, and 6L show the respective spectra of the product ions acquired while applying a magnetic field of 0.1 mT to the field-free ion drift region of the TOF mass analyzer.

[0088] FIGS. 6M, 6N, 60 and 6P show the respective spectra of the product ions acquired while applying a magnetic field of 0.3 mT to the field-free ion drift region of the TOF mass analyzer.

[0089] FIGS. 6Q, 6R, 6S, and 6T show the respective spectra of the product ions acquired while applying a magnetic field of 1 mT to the field-free ion drift region of the TOF mass analyzer.

[0090] FIGS. 6U, 6V, 6W, and 6X show the respective spectra of the product ions acquired while applying a magnetic field of 7 mT to the field-free ion drift region of the TOF mass analyzer.

[0091] The data shows that an increase in the strength of the applied magnetic field resulted in a shift in the noise “bumps” from MCP chi to MCP ch4 (See, FIGS. 6E - 6L), and the bumps were swept out when the magnetic field was stronger than 0.3 mT (FIGS. 6M-6X).

[0092] Some remaining background noise was observed in MCP chi after sweeping out of the electron noise bump (See, FIGS. 6M, 6Q, and 6U) The origin of this background is believed to be ionic, e.g., ions generated via crushing of ions by the meshes or residual gas in the TOF vacuum chamber.Y1

[0093] Example 4

[0094] FIG. 7 shows calculated trajectories of electrons with an energy of 8 keV during their transit from the second ion mirror of the TOF mass analyzer 100 discussed above to its ion detector under different magnetic field conditions. More specifically, the trajectories were calculated for the following cases: (1) no magnetic field, (2) a magnetic field of 0.06 mT, (3) a magnetic field of 0.1 mT, (4) a magnetic field of 0.3 mT, and (5) a magnetic field of 1 mT.

[0095] As seen in the depicted electron trajectories, with no magnetic field applied to the field-free ion drift region, the electrons strike the ion detector. Although the application of a magnetic field at magnitudes of 0.06 mT and 0.1 mT cause some deflection of the electrons, in this example, such low magnetic field strengths do not appear to be sufficient to provide a significant reduction in the number of electrons striking the ion detector. In other words, in this example, such low magnetic field strengths do not appear to provide a significant reduction in the noise artifacts caused by the electrons striking the ion detector. However, the electron trajectories show that as the magnetic field strength increases to 0.3 mT and particularly to 1 mT, the electrons appear to be sufficiently deflected from their original trajectories to miss the ion detector.

[0096] The above electron trajectories are consistent with the spectral features observed in the mass spectra shown in FIGS. 6A- 6X. In particular, as the strength of the applied magnetic field increases, a decrease in the noise artifacts associated with the electrons is observed.

[0097] Example 5

[0098] The data presented in FIGS. 8A and 8B were obtained using a N42-grade neodymium magnet with the following dimensions: 1.5” x 0.25” x 0.0625”. The magnetic field strength was controlled by adjusting the number of stacked magnets. The magnet stack was placed outside the TOF vacuum chamber of a Sciex Zeno TOF 7600 mass spectrometer at the location shown in FIG. 2A (as B) with the magnet’s South pole facing the ions’ flight path.

[0099] FIG. 8A shows an electron bump spectrum, where the flying ions were clusters of sodiated trifluoroacetic acid: CnHOnFisNas with m / z = -792. In region 1, electrons are produced by ion mirror 1 . In region 3 and 4, electrons are produced by mirror 2 (e.g., at positions designated as “c” and “d” in FIG. 4B).

[0100] FIG. 8B shows normalized “bump” intensities for each region, where the intensities were normalized to 100% relative to the non-magnet cases.

[0101] The data shows that the use of a single magnet (i.e., no stacking) resulted in a weaker electron noise “bump” but with the “bump” remaining. The use of two stacked magnets resulted in the noise “bump” becoming negligibly small in regions 2, 3, and 4 but still remaining in region 1. The use of three stacked magnets resulted in all electron noise “bumps” becoming negligibly small. The use of four stacked magnets did not result in any perceptible additional reduction in the background noise.

[0102] When the direction of the magnet (and hence the applied magnetic field) was reversed, even the use of four stacked magnets did not result in removing all electron noise “bumps” (See, FIG. 8B). Referring to FIG. 2A, in such cases, because source of the electrons (i.e., mirror 2) is located on the left side of the ion detector when the electrons are swept toward right hand side (e.g., when the N pole of the magnet faces the flight path), a stronger magnetic field would be needed to remove the electron noise completely.

[0103] As used herein the term "and / or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as " / ". Although some aspects have been described in the context of an apparatus, it is clear that these aspects also represent a description of the corresponding method, where a block or device corresponds to a method step or a feature of a method step. Analogously, aspects described in the context of a method step also represent description of a corresponding block or item or feature of a corresponding apparatus. Some or all of the method steps may be executed by (or using) a hardware apparatus, like for example, a processor, a microprocessor, a programmable computer or an electronic circuit. In some embodiments, some one or more of the most important method steps may be executed by such an apparatus.

[0104] Depending on certain implementation requirements, embodiments of the invention can be implemented in hardware and / or in software. The implementation can be performed using a non-transitory storage medium such as a digital storage medium, for example a floppy disc, a DVD, a Blu-Ray, a CD, a ROM, a PROM, and EPROM, an EEPROM or a FLASH memory, having electronically readable control signals stored thereon, which cooperate (or are capable ofcooperating) with a programmable computer system such that the respective method is performed. Therefore, the digital storage medium may be computer readable.

[0105] While various embodiments have been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive; embodiments of the present disclosure are not limited to the disclosed embodiments. Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing embodiments of the present disclosure, from a study of the drawings, the disclosure, and the appended claims.

[0106] In the claims, the word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality. A single processor or other processing unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measured cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0107] Those having ordinary skill in the art will appreciate that various changes can be made to the above embodiments without departing from the scope of the present teachings.

Claims

What is claimed is:

1. A time-of-flight (TOF) mass analyzer, comprising: an input for receiving a plurality of ions, an ion acceleration region through which the received ions are accelerated, a push electrode for directing the received ions into the ion acceleration region, a field-free ion drift region for receiving said accelerated ions, said field- free ion drift region having an ion detector positioned at a distal end thereof, and at least one magnet positioned relative to the electric field- free region so as to establish a magnetic field in at least a portion of the electric field-free region for deflecting electrons entering the electric field- free region so as to inhibit the electrons from reaching the ion detector.

2. The TOF mass analyzer of Claim 1 , wherein said plurality of ions comprises negatively- charged ions.

3. The TOF mass analyzer of any one of Claims 1 and 2, wherein the at least one magnet generates a magnetic field with a magnitude in a range of about 0.5 mT to about 100 mT in said portion of the electric field-free region, wherein optionally the magnetic field is in a range of about 1 mT to about 10 mT.

4. The TOF mass analyzer of any one of Claims 1 and 2, wherein the magnet is oriented relative to the electric field-free region such that the magnetic field has a component along a direction orthogonal to a longitudinal direction of the electric field-free region.

5. The TOF mass analyzer of Claim 1, further comprising a chamber in which said electric field-free region is established.

6. The TOF mass analyzer of Claim 5, wherein said magnet is positioned external to said chamber.

7. The TOF mass analyzer of Claim 5, wherein said magnet is positioned within the chamber.

8. A method of operating a time of flight (TOF) mass analyzer, comprising: introducing a plurality of ions into a time-of-flight (TOF) mass analyzer, accelerating the ions in an ion acceleration region to generate accelerated ions, introducing ions into an electric field- free ion drift region at a proximal end thereof to be incident on an ion detector positioned at a distal end of the electric field-free ion drift region, and applying a magnetic field to at least a portion of the electric field-free ion drift region for deflecting electrons entering said electric field-free ion drift region so as to inhibit the electrons from reaching the ion detector.

9. The method of Claim 8, wherein said ions comprise negatively-charged ions.

10. The method of any one of Claims 8 and 9, wherein said magnetic field has at least one component along a direction perpendicular to a longitudinal axis of the field- free ion drift region.

11. The method of any one of Claims 8 and 9, wherein said magnetic field has a magnitude in a range of about 0.5 mT to about 100 mT, and wherein optionally the magnetic field has a magnitude in a range of about 1 mT to about 10 mT.

12. The method of Claim 8, wherein said magnetic field is substantially uniform over said at least a portion of the electric field-free region.

13. The method of Claim 8, wherein said magnetic field exhibits a varying magnitude over said at least a portion of the electric field-free region.

14. The method of Claim 8, wherein said magnetic field exhibits a decreasing magnitude from the proximal end of the electric field- free region to the ion detector.

15. The method of Claim 8, wherein the magnetic field is generated by a magnet positioned external to the electric field-free ion drift region.

16. The method of Claim 8, wherein the magnetic field is generated by a magnet positioned within said electric field- free ion drift region.

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