Patent Grant
10950425
This application is a national phase filing claiming the benefit of and priority to International Patent Application No. PCT/EP2017/070508, filed on Aug. 11, 2017, which claims priority from and the benefit of United Kingdom patent application No. 1613988.3 filed on Aug. 16, 2016. The entire contents of these applications are incorporated herein by reference.
The present invention relates generally to mass spectrometers and in particular to folded flight path (FFP) spectrometers comprising electrostatic sectors.
Time-of-flight (TOF) mass spectrometers having a folded flight path (FFP) for the ions are known. These are promising instruments for achieving high mass resolution at high sensitivity and high speed of analysis. There are two main types of folded flight path TOF mass spectrometers. One type comprises two opposing ion mirrors and reflects the ions between the ion mirrors multiple times so as to provide a relatively long flight path length for the ions in a relatively small size instrument. GB 2080021 and SU 1725289 disclose examples of such instruments.
Another type of folded flight path TOF mass spectrometer comprises electrostatic sectors for bending the flight path of the ions so that a relatively long flight path can be provided in a relatively small instrument. Sakurai et al (Nucl. Instrum. Meth. A427, 1999, 182-186) and Toyoda et al (J. Mass Spectrom. 38, 2003, 1125-1142) disclose examples of such instruments.
It may be preferred to use sector-based folded flight path TOF mass spectrometers rather than ion mirror based instruments, because sector-based instruments need not have ion reflecting regions and thus may provide an order of magnitude higher space-charge tolerance. Also, sector-based instruments are able to use fewer power supplies.
On the other hand, it may be preferred to use ion mirror based folded flight path TOF mass spectrometers rather than sector-based instruments, because ion mirrors provide relatively high order time per energy focusing and thus provide the instrument with a relatively high energy acceptance. This may be important, for example, when analyzing ions from some pulsed ion sources. In contrast, conventional sector-based instruments possess only first order time per energy focusing, thus inhibiting use of sector-based analyzers in combination with some ion sources and high-field pulsed ion converters.
Another drawback of conventional sector-based folded flight path TOF mass spectrometers is that they have a relatively small spatial acceptance, i.e. the product of the accepted packet size and divergence angle is relatively small. This is especially restrictive for some instruments, for example, when used in combination with pulsed linear ion trap converters in which the phase space of the ion beam may reach 10 mm×mrad or more, even after accelerating the ions to relatively high energy.
Also, conventional sector-based folded flight path TOF mass spectrometers possess only first order time of flight focusing with respect to the spatial spread in the plane of ion deflection. In other words, the term ‘isochronous ion transport’ typically used when describing ion-optical properties of sector-based folded flight path TOF mass spectrometers, in practice, always means first order isochronous ion transport, e.g., as described by Sakurai et al (Int. J. Mass Spectrom. Ion Proc., 63, 1985, 273-287).
Another drawback of sector-based folded flight path TOF mass spectrometers is that they require relatively complex devices for ion confinement in the direction orthogonal to the plane of the curved mean ion trajectory. Conventional systems employ either toroidal sector fields or complex quadrupolar lenses. In addition to these devices being complex, they prevent operation of the instrument in many useful modes that would increase sensitivity and mass resolving power. For example, such sectors prevent the operation in an ‘open trap’ mode as described in US 2013/056627 or with reversing direction of drift in the direction perpendicular to deflection plane, similar to that disclosed in U.S. Pat. No. 5,017,780 for mirror-type sector-based folded flight path TOF mass spectrometers.
Thus, there is a need for development of simpler and less expensive sector-based folded flight path TOF mass spectrometers with increased spatial and energy acceptance and improved mass resolving power.
The present invention provides an improved mass analyser and an improved method of mass spectrometry.
The present invention provides a time-of-flight or electrostatic trap mass analyzer comprising:
an ion flight region comprising a plurality of ion-optical elements for guiding ions through the flight region in a deflection (x-y) plane;
wherein said ion-optical elements are arranged so as to define a plurality of identical ion-optical cells;
wherein the ion-optical elements in each ion-optical cell are arranged and configured so as to generate electric fields for either focusing ions travelling in parallel at an ion entrance location of the cell to a point at an ion exit location of the cell, or for focusing ions diverging from a point at the ion entrance location to travel parallel at the ion exit location;
wherein each ion-optical cell comprises a plurality of electrostatic sectors having different deflection radii for bending the flight path of the ions in the deflection (x-y) plane;
wherein the ion-optical elements in each cell are configured to generate electric fields that either (i) have mirror symmetry in the deflection plane about a line in the deflection plane that is perpendicular to a mean ion path through the cell at a point half way along the mean ion path through the cell, or (ii) have point symmetry in the deflection plane about a point in the deflection plane that is half way along the mean ion path through the cell; and
wherein the ion-optical elements are arranged and configured such that, in the frame of reference of the ions, the ions are guided through the deflection plane in the ion-optical cells along mean flight paths that are of the same shape and length in each ion-optical cell.
The inventors have recognized that using a novel combination of ion-optical symmetry, focusing conditions and electrostatic sectors having different deflection radii provides the analyzer with second order spatial isochronicity, thus providing the instrument with a relatively high spatial acceptance (i.e. the product of the accepted packet size and divergence angle is relatively large). The inventors have also realized that this provides second order energy isochronicity, thus considerably increasing their energy acceptance of the instrument. This allows the instrument to use, for example, pulsed ion sources and high-field pulsed ion converters. Embodiments provide instruments with full second order time of flight focusing with respect to the spatial spread in the deflection plane.
Sakurai et al (Nucl. Instrum. Meth. A427, 1999, 182-186) disclose a folded flight path TOF mass spectrometer comprising ion-optical elements, including electrostatic sectors. However, the ion-optical elements are not arranged in ion-optical cells, wherein each cell is capable of parallel-to-point or point-to-parallel focussing. Also, the electrostatic sectors do not have different deflection radii. As such, the analyser of Sakurai et al cannot provide the advantages of the present invention.
The skilled person will appreciate that the geometry of the ion-optical elements in the embodiments of the electrostatic sector analyser described herein defines the operating characteristics of the analyser, i.e. to achieve at least first order isochronicity in any given embodiment of the analyser, a unique set of electrical potentials must be applied to the analyser (i.e. there is single operational voltage set, rather than a plurality of sets). The geometry thus automatically defines the functions described above (e.g. repetitive cells, symmetry of the cells, and point-to-parallel and parallel-to-point focussing). For example, the deflection radii of the sectors, the angle through which each ion-optical element deflects ions, and the free flight path between adjacent ion-optical elements defines the operating characteristics of the analyser and also the voltages that must be applied to the ion-optical elements to achieve the functions described herein. The same deterministic principle linking the geometry, the voltages and the properties of sector analysers provides sufficient information for synthesis of the isochronous sector analyser based on the herein described ion optical principles. Thus, a person skilled in ion optics is capable of synthesising the proper sector system with second order isochronicity based on the principles described herein of repetitive ion cells, ion cell symmetry, parallel-to-point focusing, while using sectors with different radii. Since the principle allows synthesising a multiplicity of second order isochronous systems, we consider the set of ion optical principles as the only correct way for describing ion optics of the second order isochronous analyser.
According to the embodiments of the present invention, the ion-optical elements comprise voltage supplies and are connected to a controller. The controller and voltage supplies are set up and configured to apply voltages to the ion-optical elements so as to perform the functions described herein.
The ions may be deflected by the ion-optical elements in a substantially circular or oval loop in the deflection (x-y) plane.
The ions may be deflected by the ion-optical elements in a closed loop in the deflection (x-y) plane.
The parallel-to-point focusing, or point-to-parallel focusing, may be focusing to the first order approximation.
The analyser may be arranged and configured such that ions enter a first of the ion-optical cells as a parallel beam at the ion entrance location, or diverging from a point at the ion entrance location (to a first order approximation).
It will be appreciated that the ion entrance location and/or ion exit location of any given ion-optical cell need not correspond to a physical aperture or other physical structure, but is/are location(s) defined by the focusing of the ion optical elements in that cell (i.e. the point-to parallel or parallel-to-point focusing).
The ion-optical elements may be arranged and configured such that the ions are transmitted directly from one ion-optical cell to the next ion-optical cell. In other words, the ion exit location of any given ion-optical cell corresponds to the ion entrance location of the adjacent downstream ion-optical cell. The exit location of that downstream ion-optical cell may correspond to the ion entrance location of an ion-optical cell arranged adjacent and downstream thereof.
The analyzer may comprise only two of said ion-optical cells. Ions may be transmitted between and through these ion-optical cells only once, or a plurality of times. Alternatively, the analyzer may comprise more than two of said ion-optical cells. Ions may be transmitted between and through these ion-optical cells only once, or a plurality of times.
The ion-optical elements may be arranged and configured such that said ions travel through said ion-optical cells such that they are subjected to one or more cycle, wherein each cycle comprises either: (i) said parallel-to-point focusing by one of said cells and then said point-to-parallel focusing by another successive one of said cells; or (ii) said point-to-parallel focusing by one of said cells and then said parallel-to-point focusing by another successive one of said cells.
The ion-optical elements may be arranged and configured such that said ions are subjected to an even, integer number of said cycles.
The ion-optical elements may be arranged and configured such that, in use, said ions pass through each of said ion-optical cells in a spatially achromatic and/or energy isochronous mode to a first order approximation.
Each of said ion-optical cells may comprise at least three electrostatic sectors having at least two different deflection radii.
The mean ion path through a sector forms part of a circumference of a circle and the deflection radius of a sector is the radius defined by that circle.
The ion-optical elements may be arranged and configured in any given ion-optical cell such that for ions entering the cell as a parallel beam, the flight time of these ions through the cell is independent, to the second order approximation, of the distance of the ions from a beam ion-optic axis on entering the cell, at least in the deflection (x-y) plane.
The ion-optical elements may be arranged and configured in any given ion-optical cell so as to provide second order focusing of ion flight time with respect to energy spread in ion bunches passing through the cell.
More specifically, the ratios of sector deflection radii, sector deflection angles and sector focusing fields may be tuned to provide second order focusing of the flight time with respect to energy spread in ion bunches passing through the cell.
The electrostatic sectors may be configured to generate two-dimensional electrostatic fields for deflecting the ions in the deflection plane, wherein the fields generated by the sectors are independent of any electric fields in the direction perpendicular to the deflection plane.
The electrostatic sectors may be cylindrical sectors.
The analyser may comprise an ion accelerator for accelerating ions into the flight region and/or an ion detector for detecting ions exiting the flight region.
The analyser may comprise a drift electrode arranged and configured to cause ions to drift through the analyzer in a drift (z−) dimension perpendicular to the deflection (x-y) plane as the ions travel through the ion-optical elements.
The drift electrode may pulse ions into said flight region. The drift electrode may form at least part of an ion accelerator that accelerates ions into the flight region.
The inventors have realized that due to the significant reduction of flight time aberrations provided by the embodiments described herein, the time spread of the ion source may become a major limiting factor in the resolving power of the instrument. A relatively long flight path may be used, together with a device to avoid ion packet spreading, to overcome this.
The ion-optical elements may be arranged and configured to cause the ions to have a looped flight path in the deflection plane and to perform a plurality of loops in the deflection plane; and the analyzer may comprise one or more drift lens arranged in the flight region so that the ions pass through the one or more drift lens as the ions loop around the deflection plane, and the one or more drift lens may be configured to focus the ions in the drift (z−) dimension so as to limit the divergence of the ions in said drift dimension as they drift along the drift dimension.
The analyser may comprise a plurality of said drift lenses spaced along said drift dimension.
The plurality of said drift lenses may be arranged in a periodic array in the drift dimension.
Each of the drift lenses may be an electrostatic lens and/or may be a 2D lens.
Each of the drift lenses may focus the ions in the drift dimension in a manner that is independent of ion focusing in the deflection plane or may be configured to generate electric fields that are quadrupolar in the plane orthogonal to the deflection plane.
Each of the drift lenses may be one of: (i) a 2D lens arranged and configured so that to perform no focusing in the deflection (x-y) plane; (ii) a quadrupole lens; (iii) a combination of 2D and quadrupole lenses.
The drift lenses may be coaxial in the deflection plane.
The drift lens(es) may be arranged between sectors or may be a locally z-focusing field within at least one of the sectors.
The drift electrode may cause the ions to drift in a linear (z−) drift direction.
Alternatively, the analyzer may be arranged and configured such that the drift electrode pulses the ions to drift along a curved, e.g. circular, drift path.
The drift electrode may be arranged on a first side, in the drift (z−) dimension, of the ion-optical elements and the ion detector may be arranged on a second opposite side, in said drift dimension, of the ion-optical elements.
Alternatively, the drift electrode and ion detector may be arranged on a first side, in the drift dimension, of the ion-optical elements and one or more reflector electrode may be arranged on a second opposite side, in said drift dimension, of the ion-optical elements; wherein said reflector electrode is configured to reflect ions back in the drift dimension towards the detector.
One or more reflector electrode may be arranged on each side, in the drift dimension, of the ion-optical elements and may be configured to reflect the ions along the drift dimension as the ions pass through the ion-optical elements.
The reflector electrode(s) described herein enable ions to travel multiple times along the drift dimension, thus increasing the flight path of the ions in the analyzer and enabling higher resolving powers. The reflector electrode(s) may be supplied by a continuous or pulsed power supply.
The reflector electrode(s) described herein may be arranged and configured so as not to change the spatial focusing properties of the analyzer in the deflection (x-y) plane. However, the z-fields may affect the flight time of the ions and thus allow tuning the position of the time focus of the analyzer, i.e. may provide additional flexibility in tuning of the sector fields in the x-y deflection plane.
The drift lens(es) and reflector electrode(s) described herein do not significantly limit the resolving power of the instrument but provide significant ion flight path extension, thus compensating for higher turn-around times in an ion source, at limited energy acceptance of the analyzer.
The analyser may comprise a pulsed ion source or pulsed ion accelerator for pulsing ions into the ion-optical elements.
The relatively high spatial acceptance of the instrument enables it to be used with pulsed ion sources or pulsed ion accelerators. The pulsed ion source or ion accelerator may be any one of: a MALDI ion source; a DE MALDI ion source; a SIMS ion source; a radiofrequency axial or linear ion trap; or an orthogonal ion accelerator for accelerating ions orthogonally. For example, MALDI, SIMS, or radio frequency linear ion traps (LITs) produce ion packets with relatively low energy spreads (e.g., from 10 to 100 eV) which are particularly suitable for sector-based folded flight path TOF mass spectrometers at high transport energies, e.g., above 10 keV.
The ion accelerator may pulse ions towards a detector in a series of ion accelerator pulses, wherein the timings of the pulses are determined by an encoding sequence that varies the duration of the time interval between adjacent pulses as the series of pulses progresses; and wherein the analyser comprises a processor configured to use the timings of the pulses in the encoding sequence to determine which ion data detected at the detector relate to which ion accelerator pulse so as to resolve spectral data obtained from the different ion accelerator pulses. The ion accelerator may be configured to pulse ions towards the detector at a rate such that some of the ions pulsed towards the detector in any given pulse arrive at the detector after some of the ions that are pulsed towards the detector in a subsequent pulse. The use of the encoding sequence (i.e. an encoded frequency pulsing method) enables ions to be injected into the flight region of the analyser at time intervals that are shorter than the ion separation time in the flight region and so enables the duty cycle of the analyser to be increased.
Each of the electrostatic sectors may be a cylindrical sector having its axis of cylindrical rotation aligned in the dimension orthogonal to the deflection (x-y) plane.
The analyser may be one of:
(i) a time-of-flight mass analyzer comprising an ion accelerator for pulsing ions into said flight region and an ion detector, wherein said flight region is arranged between said ion accelerator and detector such that ions separate according to mass to charge ratio in the flight region;
(ii) an open trap mass analyzer configured such that ions enter a first end of the flight region and exit the flight region at a second, opposite end;
(iii) an electrostatic trap mass analyzer having an image current detector for detecting ions; or
(iv) an electrostatic trap mass analyzer having an ion detector arranged for detecting only a portion of the ions passing the detector.
For example, the analyzer may be an open trap mass analyser (e.g. of the type described ion WO 2011/107836) that injects ions into the analyser at one end such that the ions drift through the analyser in a z-direction orthogonal to the deflection (x-y) plane and exit the analyzer at the other end (in the z-direction) onto an ion detector. The analyser may not include drift lenses that focus the ions in the drift z-dimension (for limiting the divergence of the ions in said drift z-dimension) as they drift along the drift z-dimension. The ions may diverge in the z-dimension as they travel through the analyzer in the deflection (x-y) plane and towards the detector, and so ions may have performed different numbers of loops around the deflection (x-y) plane by the time that they reach the detector. The detector may therefore see several signals at different times for ions of the same mass to charge ratio from the same ion packet. The spectra may be interpreted using a Fourier transform technique or a multi-start encoded frequency pulsing technique (e.g. as described in WO 2011/135477).
It is also contemplated that the analyser may be an electrostatic trap mass analyzer having an image current detector for detecting ions (e.g. of the type disclosed in WO 2011/086430). The image current detector comprises at least one detection electrode and detection electronics configured to detect a current induced in the detection electrode due to ions passing proximate the detection electrode. For example, the detection electrode may be a plate electrode, or may be a tubular electrode through which the ions pass. The analyser is configured such that the ions repeatedly pass the detection electrode. The image current detector may determine, from the current induced in the detection electrode, the frequency with which ions pass the detection electrode. The analyser may then determine the mass to charge ratio of ions from the determined frequency that the ions pass the detection electrode. If ions of different mass to charge ratios are present, the different ions will pass the detection electrode with different frequencies and will induce time varying currents in the detection electrode that have different periodic frequencies. The mass to charge ratios of the different ions can be determined by determining the different periodic frequencies of the currents. As described in the above embodiments, ions may be confined and reflected in the z-direction of the analyser and so may be trapped indefinitely.
It is also contemplated that the analyser may be an electrostatic trap mass analyzer having an ion detector arranged for detecting only a portion of the ions passing the detector. The detector comprises at least one detection electrode and detection electronics configured to detect ions striking the detection electrode. The analyser is configured such that ions are repeatedly directed passed or through the detection electrode, but such that during each pass some of the ions strike the detector electrode. For example, the detection electrode may comprise a mesh or a plurality of wires through which the ions are repeatedly directed. On each pass some of the ions strike the detector electrode and the detector may determine, from the current generated in the detection electrode due to the ions striking it, the frequency with which ions pass the detection electrode. The analyser may then determine the mass to charge ratio of these ions from the determined frequency that the ions pass the detection electrode. If ions of different mass to charge ratios are present, the different ions will pass the detection electrode with different frequencies and will cause time varying currents in the detection electrode that have different periodic frequencies. The mass to charge ratios of the different ions can be determined by determining the different periodic frequencies of the currents. As described in the above embodiments, ions may be confined and reflected in the z-direction of the analyser and so may be trapped indefinitely (other than striking the detection electrode).
The present invention also provides a mass spectrometer comprising an analyzer as described herein.
The present invention also provides a method of time of flight or electrostatic trap mass analysis comprising:
transmitting ions through a flight region comprising a plurality of ion-optical elements that guide the ions in a deflection (x-y) plane;
wherein said ion-optical elements are arranged so as to define a plurality of identical ion-optical cells;
wherein the ion-optical elements in each ion-optical cell generate electric fields that either focus ions travelling in parallel at an ion entrance location of the cell to a point at an ion exit location of the cell, or focus ions diverging from a point at the ion entrance location to travel parallel at the ion exit location;
wherein each ion-optical cell comprises a plurality of electrostatic sectors having different deflection radii that bend the flight path of the ions in the deflection (x-y) plane;
wherein the ion-optical elements in each cell generate electric fields that either (i) have mirror symmetry in the deflection plane about a line in the deflection plane that is perpendicular to a mean ion path through the cell at a point half way along the mean ion path through the cell, or (ii) have point symmetry in the deflection plane about a point in the deflection plane that is half way along the mean ion path through the cell; and wherein the ion-optical elements guide the ions through the deflection plane in the ion-optical cells along mean flight paths that, in the frame of reference of the ions, are of the same shape and length in each ion-optical cell.
The method comprises applying voltages to the ion-optical elements so as to perform the functions described herein.
The method may comprise deflecting the ions, using the ion-optical elements, in a substantially circular or oval loop in the deflection (x-y) plane.
The ions may be deflected by the ion-optical elements in a closed loop in the deflection (x-y) plane.
Each of the ion-optical cells performs said parallel-to-point focusing, or point-to-parallel focusing, in the deflection plane. The parallel-to-point focusing, or point-to-parallel focusing, may be to the first order approximation.
The ions may enter a first of the ion-optical cells in the analyser as a parallel beam at the ion entrance location, or diverge from a point at the ion entrance location (to a first order approximation).
It will be appreciated that the ion entrance location and/or ion exit location of any given ion-optical cell need not correspond to a physical aperture or other physical structure, but is/are location(s) defined by the focusing of the ion optical elements in that cell (i.e. the point-to parallel or parallel-to-point focusing).
Ions may be transmitted directly from one ion-optical cell to the next ion-optical cell. In other words, the ion exit location of any given ion-optical cell may correspond to the ion entrance location of the adjacent downstream ion-optical cell. The exit location of that downstream ion-optical cell may correspond to the ion entrance location of an ion-optical cell arranged adjacent and downstream thereof.
The analyzer may comprise only two of said ion-optical cells. Ions may be transmitted between and through these ion-optical cells only once, or a plurality of times. Alternatively, the analyzer may comprise more than two of said ion-optical cells. Ions may be transmitted between and through these ion-optical cells only once, or a plurality of times.
The ions may be subjected to one or more cycle as they travel through said ion-optical cells, wherein each cycle comprises either: (i) said parallel-to-point focusing by one of said cells and then said point-to-parallel focusing by another successive one of said cells; or (ii) said point-to-parallel focusing by one of said cells and then said parallel-to-point focusing by another successive one of said cells.
The ions may be subjected to an even, integer number of said cycles.
The ions may pass through each of said ion-optical cells in a spatially achromatic and/or energy isochronous mode to a first order approximation.
Each of said ion-optical cells may comprise at least three electrostatic sectors having at least two different deflection radii.
The mean ion path through a sector forms part of a circumference of a circle and the deflection radius of a sector is the radius defined by that circle.
In any given ion-optical cell, the flight time of ions entering the cell as a parallel beam may be independent, to the second order approximation, of the distance of the ions from a beam ion-optic axis on entering the cell (at least in the deflection (x-y) plane).
Any given ion-optical cell may provide second order focusing of ion flight time with respect to energy spread in ion bunches passing through the cell. More specifically, the ratios of sector deflection radii, sector deflection angles and sector focusing fields may be tuned to provide second order focusing of the flight time with respect to energy spread in ion bunches passing through the cell.
The electrostatic sectors may generate two-dimensional electrostatic fields that deflect the ions in the deflection plane, wherein the fields generated by the sectors are independent of any electric fields in the direction perpendicular to the deflection plane.
The electrostatic sectors may be cylindrical sectors.
The method may comprise accelerating ions into the flight region using an ion accelerator and/or detecting ions exiting the flight region using an ion detector.
The method may comprise directing or deflecting ions into the flight region with a drift electrode so as to cause the ions to drift through the analyzer in a drift (z−) dimension perpendicular to the deflection (x-y) plane as the ions travel through the ion-optical elements.
The method may comprise applying a voltage pulse to the drift electrode so as to pulse ions into said flight region. The drift electrode may form at least part of an ion accelerator that accelerates ions into the flight region.
The method may comprise guiding ions in a looped flight path in the deflection plane, optionally so as to perform a plurality of loops in the deflection plane.
The method may comprise providing one or more drift lens in the flight region so that the ions pass through the one or more drift lens as the ions loop around the deflection plane.
The method may comprise applying one or more voltages to the one or more drift lens so as to focus the ions in the drift (z−) dimension, so as to limit the divergence of the ions in said drift dimension as they drift along the drift dimension.
The method may comprise providing a plurality of said drift lenses spaced along said drift dimension.
The plurality of said drift lenses may be arranged in a periodic array in the drift dimension.
Each of the drift lenses may be an electrostatic lens and/or may be a 2D lens.
Each of the drift lenses may focus the ions in the drift dimension in a manner that is independent of ion focusing in the deflection plane or may be configured to generate electric fields that are quadrupolar in the plane orthogonal to the deflection plane.
The drift lenses may be coaxial in the deflection plane.
The drift lens(es) may be arranged between sectors or may be a locally z-focusing field within at least one of the sectors.
The drift electrode may cause the ions to drift in a linear (z−) drift direction. Alternatively, the analyzer may be arranged and configured such that the drift electrode pulses the ions to drift along a curved, e.g. circular, drift path.
The drift electrode may be arranged on a first side, in the drift (z−) dimension, of the ion-optical elements and the ion detector may be arranged on a second opposite side, in said drift dimension, of the ion-optical elements.
Alternatively, the drift electrode and ion detector may be arranged on a first side, in the drift dimension, of the ion-optical elements and one or more reflector electrode may be arranged on a second opposite side, in said drift dimension, of the ion-optical elements. The method may comprise applying one or more voltages to the drift electrode (e.g. ion accelerator) so as to cause ions to drift in the drift dimension towards the reflector electrode and then applying one or more voltage to the reflector electrode so as to reflect ions back in the drift dimension towards the detector. The ions may then be detected at the deflector.
One or more reflector electrode may be arranged on each side, in the drift dimension, of the ion-optical elements. Voltages may be applied to these reflector electrodes so as to reflect the ions along the drift dimension multiple times as the ions pass through the ion-optical elements. The ions may be detected at a detector, which may be arranged on either side of the ion-optical elements.
The reflector electrode(s) described herein enable ions to travel multiple times along the drift dimension, thus increasing the flight path of the ions in the analyzer and enabling higher resolving powers. The reflector electrode(s) may be supplied by a continuous or pulsed power supply.
The reflector electrode(s) described herein may not change the spatial focusing properties of the analyzer in the deflection (x-y) plane. However, the z-fields may affect the flight time of the ions and thus allow tuning the position of the time focus of the analyzer, i.e. may provide additional flexibility in tuning of the sector fields in the x-y deflection plane.
The method may comprise pulsing ions into the ion-optical elements of the flight region using a pulsed ion source or pulsed ion accelerator.
The pulsed ion source or ion accelerator may be one of: a MALDI ion source; a DE MALDI ion source; a SIMS ion source; a radiofrequency axial or linear ion trap; or an orthogonal ion accelerator for accelerating ions orthogonally. For example, MALDI, SIMS, or radio frequency linear ion traps (LITs) produce ion packets with relatively low energy spreads (e.g., from 10 to 100 eV) which are particularly suitable for sector-based folded flight path TOF mass spectrometers at high transport energies, e.g., above 10 keV.
The ion accelerator may pulse ions towards a detector in a series of ion accelerator pulses, wherein the timings of the pulses are determined by an encoding sequence that varies the duration of the time interval between adjacent pulses as the series of pulses progresses; and a processor may use the timings of the pulses in the encoding sequence to determine which ion data detected at the detector relate to which ion accelerator pulse so as to resolve spectral data obtained from the different ion accelerator pulses. The ion accelerator may pulse ions towards the detector at a rate such that some of the ions pulsed towards the detector in any given pulse arrive at the detector after some of the ions that are pulsed towards the detector in a subsequent pulse. The use of the encoding sequence (i.e. an encoded frequency pulsing method) enables ions to be injected into the flight region of the analyser at time intervals that are shorter than the ion separation time in the flight region and so enables the duty cycle of the analyser to be increased.
The method may be a method of time-of-flight mass spectrometry comprising pulsing ions into said flight region and detecting ions leaving the flight region with an ion detector. The flight region may be arranged between the ion accelerator and detector such that ions separate according to mass to charge ratio in the flight region. The pulse time of the ion accelerator and the detection time at the ion detector, for any given ion, may be used to determine the mass to charge ratio of the ion.
The present invention also provides a method of mass spectrometry comprising a method as described herein.
The mass analysers and methods described herein are not necessarily limited to time of flight and/or electrostatic trap mass analysers.
Accordingly, the present invention also provides a mass analyzer comprising:
an ion flight region comprising a plurality of ion-optical elements for guiding ions through the flight region in a deflection (x-y) plane;
wherein said ion-optical elements are arranged so as to define a plurality of identical ion-optical cells;
wherein the ion-optical elements in each ion-optical cell are arranged and configured so as to generate electric fields for either focusing ions travelling in parallel at an ion entrance location of the cell to a point at an ion exit location of the cell, or for focusing ions diverging from a point at the ion entrance location to travel parallel at the ion exit location;
wherein each ion-optical cell comprises a plurality of electrostatic sectors having different deflection radii for bending the flight path of the ions in the deflection (x-y) plane;
wherein the ion-optical elements in each cell are configured to generate electric fields that either (i) have mirror symmetry in the deflection plane about a line in the deflection plane that is perpendicular to a mean ion path through the cell at a point half way along the mean ion path through the cell, or (ii) have point symmetry in the deflection plane about a point in the deflection plane that is half way along the mean ion path through the cell; and
wherein the ion-optical elements are arranged and configured such that, in the frame of reference of the ions, the ions are guided through the deflection plane in the ion-optical cells along mean flight paths that are of the same shape and length in each ion-optical cell.
The present invention also provides a corresponding method of mass analysis.
The spectrometer described herein may comprise an ion source selected from the group consisting of: (i) an Electrospray ionisation (“ESI”) ion source; (ii) an Atmospheric Pressure Photo Ionisation (“APPI”) ion source; (iii) an Atmospheric Pressure Chemical Ionisation (“APCI”) ion source; (iv) a Matrix Assisted Laser Desorption Ionisation (“MALDI”) ion source; (v) a Laser Desorption Ionisation (“LDI”) ion source; (vi) an Atmospheric Pressure Ionisation (“API”) ion source; (vii) a Desorption Ionisation on Silicon (“DIOS”) ion source; (viii) an Electron Impact (“EI”) ion source; (ix) a Chemical Ionisation (“CI”) ion source; (x) a Field Ionisation (“FI”) ion source; (xi) a Field Desorption (“FD”) ion source; (xii) an Inductively Coupled Plasma (“ICP”) ion source; (xiii) a Fast Atom Bombardment (“FAB”) ion source; (xiv) a Liquid Secondary Ion Mass Spectrometry (“LSIMS”) ion source; (xv) a Desorption Electrospray Ionisation (“DESI”) ion source; (xvi) a Nickel-63 radioactive ion source; (xvii) an Atmospheric Pressure Matrix Assisted Laser Desorption Ionisation ion source; (xviii) a Thermospray ion source; (xix) an Atmospheric Sampling Glow Discharge Ionisation (“ASGDI”) ion source; (xx) a Glow Discharge (“GD”) ion source; (xxi) an Impactor ion source; (xxii) a Direct Analysis in Real Time (“DART”) ion source; (xxiii) a Laserspray Ionisation (“LSI”) ion source; (xxiv) a Sonicspray Ionisation (“SSI”) ion source; (xxv) a Matrix Assisted Inlet Ionisation (“MAII”) ion source; (xxvi) a Solvent Assisted Inlet Ionisation (“SAII”) ion source; (xxvii) a Desorption Electrospray Ionisation (“DESI”) ion source; (xxviii) a Laser Ablation Electrospray Ionisation (“LAESI”) ion source; and (xxix) Surface Assisted Laser Desorption Ionisation (“SALDI”).
The spectrometer may comprise one or more ion traps or one or more ion trapping regions.
The spectrometer may comprise one or more collision, fragmentation or reaction cells.
The spectrometer may comprise a device or ion gate for pulsing ions into the flight region and/or a device for converting a substantially continuous ion beam into a pulsed ion beam for pulsing ions into the flight region.
Various embodiments will now be described, by way of example only, and with reference to the accompanying drawings in which:
As described above, folded flight path time of flight (TOF) mass spectrometers are known in which electrostatic sectors are used to bend the flight paths of the ions so that a relatively long TOF flight path can be provided in a relatively small instrument.
Various instrument geometries and ion flight paths of folded flight path TOF mass spectrometers will be described herein using Cartesian coordinates. The Cartesian coordinates are described herein such that the plane in which the electrostatic sectors bend the ion path are defined as the x-y plane, where x is the position along the ion optic axis (i.e. along the mean flight path of the ions), and y is perpendicular to this ion optic axis. The z-dimension is orthogonal to the x-y plane.
As can be seen from
However, as described in the Background section, conventional sector field folded flight path TOF mass spectrometers, such as that shown in
The analysis of aberrations can be assisted by considering the closed loop motion of the ions as periodic motion of the ions through a sequence of identical ion-optical cells, wherein each cell is considered to comprise a set of sector fields (and may optionally also comprise other ion optical elements such as ion lenses for focusing ions). For example, in
Ion trajectory projections in the x-y deflection plane can be described at each coordinate x along the ion optic axis by position vectors {y, b, τ, δ}, where: b=dyldx=tan β, β being the inclination angle of ion trajectory projection to the ion optic axis; δ=(K−K0)/K0, wherein δ is the relative deviation of the ion kinetic energy K component in the x-y deflection plane and the kinetic energy K0 component in the deflection plane for ions moving along the ion optic axis; and τ=t−t0, where r is the difference between the flight time t of the considered ion and the flight time t0 of an ion moving along the optic axis or ‘mean trajectory’.
The transformation between the position vectors performed by one cell extending from the point x=x0 and x=x1 can be described by a transfer matrix M(1): {y1, b1, τ1, δ1}=M(1){y0, b0, τ0, δ0}, where the components with the subscript 1 correspond to position x=x1 and the components with the subscript 0 correspond to position x=x0. In this case, the transport of ions through N cells is described by a product of cell transfer matrices, i.e. as follows:
M(N)=[M(1)]N (1)
It is important to emphasize that equation 1 above requires that all cells have identical electric field distributions to each other, as viewed by the ions. This requires that the mean path of the ions be bent in the same manner by each cell, as viewed from the frame of reference of the ions. For example, in
The transformation of components of the position vector by one cell can be represented by aberration expansions, as follows:
y1=Yyy0+Ybba0+Ybδ0+Yyyy02+Yyby0b0+Ybbb02+Yyδy0δ0+Ybδb0δ0+Yδδδ02+ . . . , b=Byy0+Bbb0+Bδδ0+Byyy02+Byby0b0+Bbbb02+Byδy0δ0+Bbδb0δ0+Bδδδ02+ . . . , τ1=Tyy0+Tbb0+Tδδ0+Tyyy02+Tyby0b0+Tbbb02+Tyδy0δ0+Tbδb0δ0+Tδδδ02+ . . . , δ1=δ0.
The transformation up to a particular order of aberration expansion can be expressed by the transfer matrix of this order, which is expressed through the aberration coefficients up to the same order. The general form of the second order transfer matrix is presented in the book ‘Optics of charged particles’ by H. Wollnik (Acad. Press, Orlando, 1987).
It is relatively easy to select the combination of sector fields and the drift intervals between them so as to eliminate the first order dependence of time of flight on ion energy (i.e. Tδ=0). In order to make a cell first order isochronous (Ty=Tb=0) it is also required to make the cell symmetric, either by mirror symmetry or point symmetry. The above-mentioned three conditions for first order focusing are satisfied in prior art sector based instruments. Note that due to the so-called symplectic conditions, a first order isochronous cell is always first order spatially achromatic: Yδ=Bδ=0, and vice versa.
Referring back to the prior art instrument of
As will be described in more detail below, the inventors have recognized that it is necessary for each cell to perform parallel-to-point (or point-to-parallel) of the ion beam in order to avoid certain aberrations. Accordingly, the first sector 22 and second sector 24 may be considered to form a first ion-optical cell that provides parallel-to-point focusing of the ions in the x-y deflection plane, thus eliminating aberration coefficients Yy=Bb=0. The third sector 26 and fourth sector 28 may be considered to form a second ion-optical cell that provides point-to-parallel divergence of the ion beam in the x-y deflection plane. However, as described above, equation 1 requires that all ion-optical cells have identical electric field distributions to each other, as viewed by the ions. In the analyzer of
Therefore, it will be appreciated that the prior art instruments provide first order focusing only and that second order aberration coefficients are not able to be fully eliminated.
The inventors have recognized that using a special combination of symmetry and focusing conditions in sector field based folded flight path TOF mass spectrometers, and simultaneously using electrostatic sectors with different radii, allows the ion flight time to be independent of spatial coordinates as well as independent of mixed spatial-chromatic terms in the sector field deflection plane (i.e. the x-y plane) in the second order approximation, thus considerably increasing spatial acceptance of the instrument in this plane.
Various embodiments of the present invention will now be described, which allow full independence of ion flight time from spatial coordinates in the x-y deflection plane, i.e. to eliminate all second order coefficients for the flight time expansion except for Tδδ.
As in the prior art instruments described above, it remains important for the analyzers according to the embodiments of the present invention to fulfill first order isochronicity. As described above in relation to equation 1, the sectors of the analyzers according to the embodiments of the present invention are arranged such that the motion of the ions in the x-y deflection plane can be considered to be a motion through a sequence of identical ion-optical cells.
Each cell is symmetric with respect to its middle, and the symmetry may be mirror symmetry such that the transfer matrix M(1) obeys the relationship:
M(1)=P[M(1)]−1P (2a)
where P is the reversing operator: P{y, b, τ, δ}={y, −b, −τ, δ}.
Alternatively, the symmetry may be point symmetry such that the transfer matrix M(1) obeys the relationship:
M(1)=RP[M(1)]−1PR (2b)
where R is the rotating operator: R{y, b, τ, δ}={−y, −b, τ, δ}.
The sectors are arranged and configured such that each cell is first order isochronous, as in prior art instruments, such that:
Tδ=Ty=Tb=0 (3)
The electrostatic fields in each cell are tuned such that, in the first order approximation, ions entering the cell as a parallel beam will be focused to a point at the exit (i.e. parallel-to-point focusing). As a result of the cell symmetry given by equations 2a or 2b above, this also means that the electrostatic fields in each cell are tuned such that, in the first order approximation, ions entering the cell that diverge from a point will be focused to a parallel beam at the exit (i.e. point-to-parallel focusing).
As each cell provides parallel-to-point focusing in the first order approximation (for ions entering the cell as a parallel beam), this leads to:
Yy=0 (4)
As each cell provides point-to-parallel focusing in the first order approximation (for ions diverging from a point and entering the cell), this leads to:
Bb=0 (5)
The condition of equation 4 also leads to stable, indefinite ion confinement of ions in the x-y plane, since it satisfies the stability condition −1<Yy<1. Note that some prior art sector systems such as that of
The inventors have recognized that in sector based instruments the compensation of at least one second order aberration (e.g. fulfilling the condition Tyy=0) can be reached by adding another degree of flexibility, such as by using a cell in which there are sector fields with two different deflection radii. As it is required for each cell to be symmetric, a cell having sectors of two different deflection radii must comprise at least three sectors.
Tyy=0 (6)
The ion-optical elements in the analyzer of
The projection of the ion optic axis to the xy-plane forms a closed substantially oval path. Ion motion through the analyzer can be considered as the transport of ions through a sequence of identical cells, each cell deflecting the mean ion path by 180 degrees. More specifically, sectors 30-32 can be considered to form a first cell and sectors 33-35 can be considered to form a second cell. The sectors in each cell are arranged and configured to perform parallel-to-point focusing of the ions (or point-to-parallel focusing). Each cell also has mirror symmetry about a line that is perpendicular to the mean ion path through the cell at the point half way along the mean ion path through the cell (in the x-y plane of deflection).
In order to compensate for at least one second order aberration, each cell comprises sectors having different deflection radii. Considering the first cell, the radius of the optic axis in the second sector 31 is 1.55 times larger than the radius of the optic axis in each of the first and third sectors 30,32. The ion deflecting angle of each of the first and third sectors 30,32 is 49 degrees. The ion deflecting angle of the second sector 31 is 82 degrees. Similarly, in the second cell, the radius of the optic axis in the fifth sector 34 is 1.55 times larger than the radius of the optic axis in each of the fourth and sixth sectors 33,35. The ion deflecting angle of each of the fourth and sixth sectors 33,35 is 49 degrees. The ion deflecting angle of the fifth sector 34 is 82 degrees. The ion deflecting angles, deflection radii, and lengths of drift spaces between the sectors are chosen such that in each cell the ion-optical conditions of equations 3-5 above are satisfied, i.e. Yy=Bb=0 and Ty=Tb=T6=0. Additionally, the use of sectors having different deflection radii in each cell enables the system to compensate for the second order aberration of equation 6 above, i.e. Tyy=0.
Although two specific examples have been described in relation to
The inventors have realized that the parallel-to-point (and point-to-parallel) geometric focusing described above in relation to equations 4 and 5 within a symmetric cell according to equations 2a or 2b has the important consequence that two second order aberration coefficients for the flight time expansion are proportional to each other, i.e. that:
Tyy=By2Tbb (7)
Thus, the compensation of one second order aberration Tyy=0 as described in relation to equation 6 automatically compensates for another proportional second order aberration such that:
Tbb=0 (8)
Accordingly, it has been recognized that each identical cell of the system is now able to be first order isochronous in accordance with equation 3, provide parallel-to-point focusing (or point-to-parallel focusing) according to equations 4 and 5, and is able to compensate for two second order aberrations according to equations 6 and 8.
The inventors have also recognized that fulfilling the above three conditions automatically allows the elimination of the rest of the second order time of flight aberrations (except for Tδδ) after passing the ions through a number of the cells. This can be shown by calculating geometric and time of flight coefficients of aberration expansions after several cells by using multiplication of the cell transfer matrices. Indeed, considering equations 4 and 5 for a single cell, the multiplication of transfer matrices as in equation 1 above gives the following first order geometric transfer matrix coefficients after two cells:
Yy(2)=Bb(2)=−1,By(2)=Yb(2)=0 (9)
The same multiplication for the time of flight coefficients shows that all of the elimination conditions of equations 3, 6 and 8 above, which are achieved for a single cell, also remain valid after two cells, i.e.:
Tδ(2)=Ty(2)=Tb(2)=Tyy(2)=Tbb(2)=0 (10)
Also, due to the conditions of equations 4 and 5 above, the mixed geometric aberration coefficient Tyb is eliminated after the ions pass through two identical cells. i.e.:
Tyb(2)=0
By multiplying two identical second order transfer matrices for two cells, it is also apparent that all time of flight coefficients that are eliminated after the ions pas through two cells (see equations 10 and 11) remain eliminated after the ions pass through four cells, i.e.:
Tδ(4)=Ty(4)=Tb(4)=Tyy(4)=Tbb(4)=Tyb(4)=0 (12)
Also, due to the conditions in equation 9, the mixed geometric-chromatic aberration coefficients are also eliminated after the ions pass through each 4 cells, i.e.:
Tyδ(4)=Tbδ(4)=0. (13)
Thus, it is clear from equations 12 and 13 that after ions pass through four successive cells all second order aberration coefficients for the flight time expansion, except for Tδδ, are eliminated.
In order to illustrate the ability of an embodiment of the present invention to compensate for aberrations, Table 1 below is presented. Table 1 shows the aberration coefficients after the ions pass through one, two and four cells in the instrument of
It can be seen from Table 1 that the only non-vanishing second order aberration after the ions pass through four successive cells is Tδδ/t0, and even then the value of this aberration is about 3 times smaller than in the prior art analyzer of
The system of
In the embodiments described above, the ions may be pulsed into the analyzer and guided along a flight path defined by the sectors. The sectors bend the flight path and hence allow a relatively long flight path to be provided in a relatively small space. When the ions have travelled a desired flight path length, e.g. when the ions have travelled through a desired number of cells of the analyzer, the ions are directed onto a detector. The duration of time between an ion being pulsed into the analyzer and the ion being detected at the detector can be used to determine the mass to charge ratio of that ion, as in conventional TOF mass analyzers. As the instruments of the present invention have a relatively long flight path length, the mass resolution of the instrument may be relatively high. The configuration of the sectors increases the flight path length per unit size of the instrument, whilst eliminating second order aberrations that would otherwise deteriorate mass analysis.
The motion of the ions around the analyzer has only been described in the x-y deflection plane. When the ions have travelled the desired flight path length they may be deflected, e.g. in a direction perpendicular to the mean flight path, onto the detector. Alternatively, the ions may be caused to drift in a direction perpendicular to the x-y plane (i.e. the z-direction) as they pass around the analyzer in the x-y plane. The ion detector may be arranged at a position in the z-direction such that after a predetermined flight path (e.g., after a predetermined number of loops in the x-y place) the ions have travelled a distance in the z-direction such that the ions impact on the ion detector.
The analyser may also comprise periodic drift lenses 66 for confining ions in the z-direction. The drift lenses 66 focus ions in the z-direction and thus maintain the ion packets at a desired x-position as they loop around the analyzer in the x-y plane. The electric fields of the periodic lenses 64 may not focus or disperse the ions in the x-y plane but, e.g. by inducing an accelerating or retarding field, allow tuning a position of the final time focus at the detector 64. Note that in contrast to periodic lenses used in ion mirror based multi-reflecting time of flight mass spectrometers, in sector field instruments ions can pass through periodic lenses only once per loop. Although z-direction periodic lenses 66 are only shown between sectors 32 and 33 it is contemplates that these lenses, or additional such lenses, may be arranged between any other pair of sectors such as between sectors 30 and 35. Periodic lenses may be arranged between more than one pair of sectors so as to provide for tighter ion confinement in the z-direction. The periodic lenses may produce a two-dimensional focusing field, may be coaxial lenses, or may have an adjustable quadrupolar field component for adjustments of ion trajectories in the x-y plane.
At a simulated resolving power of R=200,000, embodiments of the present invention have an acceptance over 30 mm x mrad, while prior art sector based instruments have an acceptance of less than 3 mm x mrad. The embodiments of the present invention therefore accommodate ion sources having relatively great emittances, such as SIMS and DE MALDI sources, which tend to have emittances between 3 and 10 mm x mrad. The embodiments are also able to accommodate radio-frequency linear ion traps well, which tend to have larger emittances, e.g., emittances of at least 10 mm x mrad. The embodiments also have a relatively high tolerance to space charge effects (the analyzer tolerates ion packets spatial expansion), and an ability to reach higher resolving powers for ion sources with limited emittance. Compact analyzers or ion guides may also be used to match an ion sources emittance with the analyzer acceptance.
Although the present invention has been described with reference to preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made without departing from the scope of the invention as set forth in the accompanying claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 1613988 | Aug 2016 | GB | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2017/070508 | 8/11/2017 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2018/033494 | 2/22/2018 | WO | A |
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