Multi-reflecting time-of-flight mass spectrometer and method of use Number:7,385,187 from the United States Patent and Trademark Office (PTO) owispatent A multiple reflecting time-of-flight mass spectrometer (MR-TOF MS) and method of analysis are disclosed. The flight path of ions is folded along a trajectory by electrostatic mirrors. The longer flight path provides higher resolution while maintaining a moderate instrument size.<H spectrometer, reflecting, Multi, reflectin, 7385187.html, Patent, pto, 7385187

Title: Multi-reflecting time-of-flight mass spectrometer and method of use

Abstract: A multiple reflecting time-of-flight mass spectrometer (MR-TOF MS) and method of analysis are disclosed. The flight path of ions is folded along a trajectory by electrostatic mirrors. The longer flight path provides higher resolution while maintaining a moderate instrument size.

Patent Number: 7,385,187 Issued on 06/10/2008 to Verentchikov, et al.

Inventors: Verentchikov; Anatoli (St. Petersburg, RU), Yavor; Mikhail (St. Petersburg, RU), Mitchell; Joel C. (Bridgman, MI), Arteav; Viatcheslav (St. Joseph, MI)
Assignee: Leco Corporation (St. Joseph, MI)

Appl. No.: 10/561,775

Filed: June 18, 2004

PCT Filed: June 18, 2004

PCT No.: PCT/US2004/019593

371(c)(1),(2),(4) Date: December 20, 2005

PCT Pub. No.: WO2005/001878

PCT Pub. Date: January 06, 2005

Foreign Application Priority Data


Jun 21, 2003 [GB]			0314568.7

Current U.S. Class: 250/287 ; 250/281; 250/282; 250/283; 250/294; 250/298

Field of Search: 250/287,281,282,283,294,298

References Cited [Referenced By]

U.S. Patent Documents


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4963736	October 1990	Douglas et al.
5017780	May 1991	Kutscher et al.
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5763878	June 1998	Franzen
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6020586	February 2000	Dresch et al.
6107625	August 2000	Park
6111250	August 2000	Thomson et al.
6331702	December 2001	Krutchinsky et al.
6504150	January 2003	Verentchikov et al.
6545268	April 2003	Verentchikov et al.
6670606	December 2003	Verentchikov et al.
6674069	January 2004	Martin et al.

Foreign Patent Documents


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2080021	Jul., 1981	GB
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WO 9103071	Mar., 1991	WO
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WO 2004008481	Jan., 2004	WO

Other References

Benjamin M. Chien, et al., "Plasma Source Atmospheric Pressure Ionization Detection of Liquid Injection Using an Ion Trap Storage/Reflectron Time-of-flight Mass Spectromerty," Anal. Chem. 1993, 65, 1916-1924. cited by other .
John B. Hoyes, et al., "A High Resolution Orthogonal TOF with Selectable Drift Length," ASMS2000. cited by other .
Qinchung Ji, et al., "A Segmented Ring, Cylindrical Ion Trap Source for Time-of-flight Mass Spectrometry," J Am Soc Mass Spectrom 1996, 7, 1009-1017. cited by other .
Alfonz Luca, et al., "On the combination of a Linear Field Free Trap with a TOF MS," 2001 American Institute of Physics, Review of Scientific Instruments, vol. 72 No. 7, Jul. 2001, pp. 2900-2908. cited by other .
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H. Wollnik and M. Przewloka, "Time-of-Flight Mass Spectrometers with Multiply Refelcted Ion Trajectories," International Journal of Mass Spectrometery and Ion Processes, vol. 96, No. 3, pp. 267-274, (Apr. 16, 1990). cited by other .
H. Wollnik, A. Casares, "An Anergy-isochronous Multi-pass TOF MS Consisting of Two Coaxial Electrostatic Mirrors," International Journal of Mass Spectrometry 227 (2003) pp. 217-222. cited by other .
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Primary Examiner: Kim; Robert
Assistant Examiner: Maskell; Michael
Attorney, Agent or Firm: Price, Heneveld, Cooper, DeWitt & Litton, LLP

Claims

The invention claimed is:

1. A multi-reflecting time-of-flight mass spectrometer (MR-TOF MS) comprising: an ion source; an ion receiver downstream from said ion source; at least one ion mirror assembly intermediate said ion source and said ion receiver and elongated in a shift direction for improving sensitivity and resolution of the MR-TOF MS; a drift space intermediate said ion mirror assembly; and a lens assembly disposed within said drift space along said at least one shift direction and with a period in said shift direction corresponding to ion shift per integer number of ion reflections, said ion source, ion receiver, ion mirror assembly and said drift space arranged to provide a folded ion path between said ion source and said ion receiver composed of at least one reflection by said ion mirror assembly for separating ions in time according to their mass-to-charge ratio (m/z) so that a flight time of the ions is substantially independent of ion energy.

2. The MR-TOF MS as defined in claim 1, further comprising: a timed ion selector including one of a Bradbury-Nielsen ion gate, a parallel plate deflector, and a control grid within said ion receiver.

3. The MR-TOF MS as defined in claim 1, wherein said ion source comprises one of an ion storage device and an ion accelerator.

4. The MR-TOF MS as defined in claim 1, wherein said ion source comprises a continuous ion source.

5. The MR-TOF MS as defined in claim 1, wherein said ion source comprises one of a SIMS, a MALDI, and an IR-MALDI.

6. The MR-TOF MS as defined in claim 4, wherein said ion source comprises one of an ESI, an APCI, an APPI, an EI, a CI, a PI, an ICP, a gas-filled MALDI, an atmospheric MALDI, a gaseous ion reaction cell, a DC/field asymmetric ion mobility spectrometer, and a fragmentation cell.

7. The MR-TOF MS as defined in claim 1, wherein said ion receiver includes an ion detector having an extended dynamic range.

8. The MR-TOF MS as defined in claim 1, wherein said ion receiver comprises a gas-filled cell selected from one of a fragmentation cell, a molecular reaction cell, an ion reaction cell, electron capture dissociation, ion capture dissociation, a soft deposition cell, and a cell for surface ion dissociation.

9. A multi-reflecting time-of-flight mass spectrometer (MR-TOF MS) comprising: an ion source; an ion receiver downstream from said ion source; at least one ion mirror assembly intermediate said ion source and said ion receiver and elongated in a shift direction for improving sensitivity and resolution of the MR-TOF MS; and a drift space intermediate said ion mirror assembly, said ion source, ion receiver, ion mirror assembly and said drift space arranged to provide a folded ion path between said ion source and said ion receiver composed of at least one reflection by said ion mirror assembly for separating ions in time according to their mass-to-charge ratio (m/z) so that a flight time of the ions is substantially independent of ion energy, wherein said ion mirror assembly comprises a plurality of electrodes shaped and spaced relative to one another to provide a spatial ion focusing and time-of-flight focusing of ions substantially independent of ion energy and on ion position in a plane transverse to said ion path.

10. The MR-TOF MS as defined in claim 1, wherein said ion mirror assembly includes one of a parallel assembly of conductive square frames, slotted plates, bars, and rods, each having an optional edge termination.

11. The MR-TOF MS as defined in claim 1, wherein at least a portion of said ion mirror assembly is operably connected to a pulsed voltage supply for gating ions in or out of the MR-TOF MS.

12. The MR-TOF MS as defined in claim 1, wherein said ion mirror assembly comprises at least two electrodes having voltages of opposite polarities relative to the other to form an attractive lens.

13. The MR-TOF MS as defined inclaim 1, wherein said drift space comprises an ion deflector connected to one of a DC voltage supply and a pulsed voltage supply.

14. The MR-TOF MS as defined in claim 1, wherein said lens assembly includes at least two lenses elongated transversely to said ion path.

15. The MR-TOF MS as defined in claim 3, wherein said ion storage device comprises a gas-filled set of electrodes having a radio-frequency (RF) voltage applied to at least one of said electrodes.

16. The MR-TOF MS as defined in claim 3, wherein said ion storage device comprises a plurality of sets of electrodes having a radio frequency (RF) voltage applied to at least one electrode in a first set of electrodes and a pulse voltage applied to at least one electrode in a second set of electrodes.

17. The MR-TOF MS as defined in claim 3, wherein said ion accelerator comprises a pulsed orthogonal accelerator.

18. The MR-TOF MS as defined in claim 3, wherein said ion accelerator comprises a plurality of electrodes, each having a slit along said shift direction of the MR-TOF MS.

19. The MR-TOF MS as defined in claim 3, wherein said ion accelerator comprises one of a pulsed ion mirror assembly and a pulsed portion of said ion mirror assembly.

20. The MR-TOF MS as defined in claim 3, wherein said ion accelerator comprises one of an accelerator with pulsed voltages and an accelerator with static voltages.

21. The MR-TOF MS as defined in claim 4, wherein said continuous ion source comprises an intermediate ion storage guide preceding said ion storage device and having a gas pressure greater than said ion storage device.

22. The MR-TOF MS as defined in claim 4, wherein said continuous ion source comprises at least two gas-filled sets of electrodes having a radio-frequency (RF) voltage applied to at least one set of said gas-filled electrodes.

23. The MR-TOF MS as defined in claim 7, wherein said ion detector comprises one of a secondary electron multiplier having at least one dynode, a scintillator and photomultiplier, a micro-channel, micro-sphere plates, at least two channels of detection, and at least two anodes each connected to a data acquisition system having an analog-to-digital converter (ADC).

24. The MR-TOF MS as defined in claim 7, wherein said ion detector dynamic range is extended by alternating scans with various intensities of said pulsed ion source.

25. The MR-TOF MS as defined in claim 7, wherein said ion detector dynamic range is extended by alternating scans with varying durations of ion injection into an ion storage device.

26. The MR-TOF MS as defined in claim 8, wherein said gas-filled cell includes at least one electrode connected to a radio-frequency (RF) voltage for one of dampening ion kinetic energy in gas collisions, stabilizing internal ion energy, confining ions, fragmenting ions, selecting ion species and retaining ions for exposure to reactant particles.

27. The MR-TOF MS as defined in claim 13, wherein said ion deflector comprises at least one steering plate.

28. The MR-TOF MS as defined in claim 13, wherein said ion deflector is located on a far side of said shift axis opposite to said ion source for steering ions in a static mode to change direction of said ion path.

29. The MR-TOF MS as defined in claim 13, wherein said ion deflector is located on a similar side of said shift axis as said ion source for directing ions toward one of an off-axis detector and an MR-TOF MS analyzer, and revert in a direction of ion shift for a time of ion confinement within the MR-TOF MS.

30. The MR-TOF MS as defined in claim 15, wherein said gas-filled set of electrodes comprises at least one of an ion guide having a plurality of elongated rods, a 3-D quadrapole ion trap, a linear ion trap with ion ejection, an RF channel with at least one electrode having an opening for ion passage, a ring electrode trap, a hybrid ion guide with a 3-D ion trap, and a segmented analog of the aforementioned electrodes formed of at least two plates.

31. The MR-TOF MS as defined in claim 4, wherein said ion storage device includes one of a filter of ion components, a discriminator of ion components, and a suppressor of ion components.

32. A tandem time-of-flight mass spectrometer apparatus, comprising: a pulsed ion source; said MR-TOF MS of claim 1 provided to separate parent ions; a fragmentation cell downstream of said MR-TOF MS for fragmenting the parent ions into daughter ions; and a mass spectrometer downstream of said fragmentation cell for detecting said daughter ions; wherein said at least one ion mirror assembly comprises two grid-less and parallel ion mirrors separated by a drift space and substantially elongated in one shift-direction.

33. The mass spectrometer apparatus as defined in claim 32, further comprising an ion selector subsequent said fragmentation cell.

34. The mass spectrometer apparatus as defined in claim 32, wherein said fragmentation cell comprises a gas-filled cell having a differential pumping stage and an ion focusing device.

35. The mass spectrometer apparatus as defined in claim 32, wherein said fragmentation cell comprises an internal gas pressure P associated with a cell length L (P*L) above 0.2 Torr*cm.

36. The mass spectrometer apparatus as defined in claim 32, wherein said fragmentation cell comprises a gas pressure P>0.5 Torr and L<1 cm.

37. The mass spectrometer apparatus as defined in claim 32, wherein said fragmentation cell comprises a gas filled set of electrodes having a radio frequency (RF) voltage applied to at least one of said electrodes for confining ions in radial direction.

38. The mass spectrometer apparatus as defined in claim 32, wherein said fragmentation cell further comprises a set of electrodes connected to one of a DC and slow-varying voltage to form an axial DC electric field, and an axial moving-wave electric field to control velocity of ion motion in said fragmentation cell, said DC voltage being applied to one of the same set of electrodes and a dissimilar set of electrodes.

39. The mass spectrometer apparatus as defined in claim 32, wherein said mass spectrometer downstream of said fragmentation cell comprises a time-of-flight mass spectrometer (TOF MS).

40. The mass spectrometer apparatus as defined in claim 39, wherein said TOF MS comprises an orthogonal ion accelerator.

41. The mass spectrometer apparatus as defined in claim 39, wherein said TOF MS comprises ion path less than, and an acceleration voltage greater than in said MR-TOF MS to produce an ion flight time in said TOF MS at least 100-fold less than in said MR-TOF MS.

42. The mass spectrometer apparatus as defined in claim 39, wherein said TOF MS comprises a data system adapted for parallel acquisition of daughter spectra without mixing spectra corresponding to different parent ions.

43. The mass spectrometer apparatus as defined in claim 39, wherein said TOF MS includes a first and a second multi-reflecting time-of-flight mass spectrometer (MR-TOF MS).

44. The mass spectrometer apparatus as defined in claim 43, wherein said second MR-TOF MS is substantially identical in construction to said first MR-TOF MS.

45. The mass spectrometer apparatus as defined in claim 40, wherein said orthogonal ion accelerator is grid-less.

46. The mass spectrometer apparatus as defined in claim 44, wherein the second MR-TOF MS forming said TOF MS comprises a plurality of deflectors cooperating with lenses in said drift space to adjust a flight path of the ions in said TOF MS.

47. A tandem multi-reflecting time-of-flight mass spectrometer (MR-TOF MS-MS) apparatus comprising: a first multi-reflecting time-of-flight mass spectrometer (MR-TOF MS) for separating parent ions; a fragmentation cell attached to said first MR-TOF MS for receiving said parent ions; and a second MR-TOF MS attached to said fragmentation cell for mass analysis of daughter ions exiting said fragmentation cell, wherein at least one of said MR-TOF MS comprises at least two grid-less and parallel ion mirrors separated by drift space and substantially elongated in one shift-direction, wherein at least one of said first and second MR-TOF MS comprises: an ion source; an ion receiver downstream from said ion source; at least one ion mirror assembly intermediate said ion source and said ion receiver and elongated in a shift direction for improving sensitivity and resolution of the MR-TOF MS; a drift space intermediate said ion mirror assembly; and a lens assembly disposed within said drift space along said at least one shift direction and with a period in said shift direction corresponding to ion shift per integer number of ion reflections, said ion source, ion receiver, ion mirror assembly and said drift space arranged to provide a folded ion path between said ion source and said ion receiver composed of at least one reflection by said ion mirror assembly for separating ions in time according to their mass-to-charge ratio (m/z) so that a flight time of the ions is substantially independent of ion energy.

48. The tandem MR-TOF MS-MS apparatus as defined in claim 47, further comprising a timed ion selector between said first MR-TOF MS and said fragmentation cell.

49. The tandem MR-TOF MS-MS apparatus as defined in claim 47, wherein said fragmentation cell further comprises at least one set of electrodes connected to one of DC and slow varying voltage to form one of a respective axial DC electric field or an axial moving-wave electric field, controlling velocity of ion motion within said fragmentation cell, and said DC voltage being applied to at least one electrode in said at least one set as RF voltage.

50. The tandem MR-TOF MS-MS apparatus as defined in claim 47, wherein said fragmentation cell further includes a gas at a gas pressure (P) above P*L>0.2 Torr*cm.

51. The tandem MR-TOF MS-MS apparatus as defined in claim 47, wherein said fragmentation cell comprises a differential pumping stage and an ion focusing assembly.

52. The tandem MR-TOF MS-MS apparatus as defined in claim 47, wherein said fragmentation cell comprises at least one gas-filled set of electrodes having a radio frequency (RF) voltage applied to at least one electrode within said set of electrodes to confine ions in a radial direction.

53. The tandem MR-TOF MS-MS apparatus as defined in claim 47, wherein said fragmentation cell comprises means for ion storage and pulsed ejection in one of an axial and an orthogonal direction.

54. The tandem MR-TOF MS-MS apparatus as defined in claim 50, wherein said second TOF MS comprises an orthogonal ion accelerator.

55. The tandem MR-TOF MS-MS apparatus as defined in claim 53, wherein said second MR-TOF MS comprises means for adjusting an ion path less than, and an acceleration voltage greater than, said first MR-TOF MS such that a flight time in said TOF MS is at least 100-fold less compared to said flight time in said first MR-TOF MS.

56. The tandem MR-TOF MS-MS apparatus as defined in claim 52, wherein said second MR-TOF MS comprises a data system providing parallel acquisition of daughter spectra without mixing spectra from unrelated parent ions.

57. The tandem MR-TOF MS-MS apparatus as defined in claim 56, wherein said second MR-TOF MS comprises a lens assembly disposed within said drift space.

58. The tandem MR-TOF MS-MS apparatus as defined in claim 57, wherein said lens assembly comprises at least one deflector configured to adjust a flight path of ions in said second MR-TOF MS.

59. A multi-reflecting time-of-flight mass spectrometer (MR-TOF MS-MS) apparatus comprising: a multi-reflecting time-of-flight mass spectrometer (MR-TOF MS); and a fragmentation cell connected to said MR-TOF MS and configured to revert ions within said MR-TOF MS to employ the same MR-TOF analyzer for analysis of both parent ions and fragment ions, wherein said MR-TOF MS comprises an assembly of two grid-less and parallel ion mirrors separated by drift space and substantially elongated in one shift-direction, wherein said MR-TOF MS comprises: an ion source; an ion receiver downstream from said ion source; at least one ion mirror assembly intermediate said ion source and said ion receiver and elongated in a shift direction for improving sensitivity and resolution of the MR-TOF MS; a drift space intermediate said ion mirror assembly; and a lens assembly disposed within said drift space along said at least one shift direction and with a period in said shift direction corresponding to ion shift per integer number of ion reflections, said ion source, ion receiver, ion mirror assembly and said drift space arranged to provide a folded ion-path between said ion source and said ion receiver composed of at least one reflection by said ion mirror assembly for separating ions in time according to their mass-to-charge ratio (m/z) so that a flight time of the ions is substantially independent of ion energy.

Description

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention generally relates to the area of mass spectroscopic analysis, and in particular to a multi reflecting time-of-flight mass spectrometer (MR-TOF MS) and a method of use.

2. State of the Art

Mass spectrometry is a well recognized tool of analytical chemistry, used for identification and quantitative analysis of various compounds and mixtures. The sensitivity and resolution of such analysis is an important concern for practical use. It has been well recognized that resolution of TOF MS is proportional to the length of the flight path. However, it is recognized it is difficult to increase the flight path while keeping the instrument to a reasonable size. A proposed solution is multi-reflecting time-of-flight mass spectrometers (M-TOF MS). The use of MR-TOF MS became possible after the introduction of an electrostatic ion mirror with time-of-flight focusing properties. U.S. Pat. No. 4,072,862, Soviet Patent No. SU198034 and Sov. J. Tech. Phys. 41 (1971) 1498 disclose an ion mirror to improve the focusing of ion energy in time-of-flight instruments. The use of the ion mirror automatically causes a single folding of ion flight path.

H. Wollnik realized a potential of ion mirrors for implementing a multi-reflecting MR-TOF MS. United Kingdom Patent No. GB2080021 suggests a way of reducing the full length of an instrument by folding the ion path between multiple gridless mirrors. Two rows of such mirrors may be aligned in the same plane or located on two opposite parallel circles (FIG. 1). Introduction of gridless ion mirrors with spatial ion focusing was intended to reduce ion losses and keep the ion beam confined regardless of the number of reflections (more details in U.S. Pat. No. 5,017,780). The gridless mirrors disclosed in GB 2080021 were to provide independence of ion flight time from the ion energy. Two types of MR-TOF MS are disclosed: (a) folded path` scheme, which is equivalent to combining N sequential reflecting TOF MS, and where the flight path is folded along a jig-saw trajectory; and (b) `coaxial reflecting` scheme, which employs multiple ion reflections between two axially aligned ion mirrors using pulsed ion admission and release. The `coaxial reflecting` scheme was also described by H. Wollnik et al. in Mass Spec. Rev., 1993, 12, p.109 and was implemented in the work published in the Int. J. Mass Spectrom. Ion Proc. 227 (2003) 217. Resolution of 50,000 was achieved after 50 turns in a moderate size (30 cm) TOF MS. Gridless and spatially focusing ion mirrors indeed preserved ions of interest (losses were below factor of 2), though the admitted mass range shrank proportionally with the number of cycles.

Another type, cyclic MR-TOF MS was described in papers by H. Wollnik, Nucl. Instr. Meth., A258 (1987) 289, and Sakurai et al, Nucl. Instr. Meth., A427 (1999) 182. Ions are kept in closed orbits using electrostatic or magnetic deflectors. The scheme employed multiple repetitive cycles, which shrank mass range, similarly to the coaxial reflecting scheme.

A folded path MR-TOF MS using two-dimensional gridless mirrors was disclosed in Soviet Union Patent SU1725289. The MR-TOF MS comprised two identical mirrors, built of bars, were parallel and symmetric with respect to the median plane between the mirrors and also to the plane of the folded ion path (FIG. 2). Mirror geometry and potentials were arranged to focus the ion beam spatially across the plane of the folded ion path and provide second-order time of flight focusing with respect to the ion energy. The ions experienced multiple reflections between the planar mirrors, while slowly drifting towards the detector in a so-called shift direction (here X-axis). The number of cycles and resolution were adjusted by varying the ion injection angle.

Nazarenko's prototype of a `folded path` MR-TOF MS with planar gridless mirrors, having spatial and time-of-flight focusing properties did not provide ion focusing in the shift direction, thus limiting the number of reflection cycles. Besides, the ion mirrors used in the prototype did not provide time-of-flight focusing with respect to spatial ion spread across the plane of the folded ion path, so that a use of diverging or wide beams would in fact ruin the time-of-flight resolution and would make an extension of flight path pointless. In other words, the scheme failed to deliver an acceptable analyzer and thus the ability of working with real ion sources. Lastly, the Nazarenko prototype has no implication on the type of ion source, nor on efficient ways of coupling between MR-TOF MS and various ion sources,

The type of ion source, its spatial and timing characteristics of ion beam, as well as geometrical constrains are the important considerations in the design of MR-TOF MS. Compatibility with single reflecting TOF MS does not automatically mean that a source is well suited for MR-TOF MS. For example, pulsed ion sources, like secondary ion SIMS or matrix-assisted desorption/ionization MALDI, are very compatible with TOF MS and such instruments are characterized by high resolution and moderate ion losses caused by spatial ion divergence. Switching to MR-TOF MS introduces new problems. On one hand, a pulsed nature of such sources suits well an extension of flight time in MR-TOF MS since frequency of ionizing pulses is adjustable. On the other hand, instability of MALDI ions is a limiting factor on flight time extension.

Gaseous ion sources, like electrospray (ESI), atmospheric pressure chemical ionization (APCI) atmospheric pressure photo-ionization (APPI), electron impact (EI), chemical ionization (CI), photo-ionization (CI) or inductively-coupled plasma (ICP) are known to produce stable ions, but they generate intrinsically continuous ion beams, or quasi-continuous ion beams, as in case of recently introduced gas filled MALDI ion source described in U.S. Pat. Nos. 6,331,702, and 6,504,150. TOF MS has been successfully coupled with continuous, and later to quasi-continuous ion sources, after introduction of an orthogonal ion acceleration scheme (o-TOF MS) (see U.S. Pat. No. 5,070,240, WO9103071, Soviet patent SU1681340), efficiently converting continuous ion beams into ion pulsed packets. Gaseous ion sources in combination with a collisional-cooling ion guide (U.S. Pat. No. 4,963,736) produce cold ion beams with low velocity spread along the axis of TOF MS, which help to achieve high TOF resolution in excess of 10,000. However, using MR-TOF MS would reduce the duty cycle of orthogonal acceleration and thus drop sensitivity.

U.S. Pat. No. 6,107,625 suggests that a further increase of resolution of o-TOF MS is mostly limited by a so-called `turn-around time` and increasing of flight path improves resolution. The '625 patent suggests a coupling of external ESI source to a `coaxial reflecting` MR-TOF MS via an orthogonal accelerator, combined with an ion mirror and multiple deflectors, such as shown in FIG. 3. To improve the sampling of the continuous ion beam, the interface employs a linear ion trap, storing ions between rare ion pulses. Melvin Park et. al. in the article entitled `Analytical Figure of Merits of a Multi-Pass Time-of-Flight Mass Spectrometer`, extended abstract on ASMS 2001, www.asms.org, MR-TOF MS demonstrated resolution of 60,000 using 6 cycles of reflections in a c.a. 1 m long instrument. However, the use of ion mirrors with grids caused severe ion scattering and ion losses. Coaxial reflecting MR-TOF MS improved resolution but shrank mass range proportionally.

ESI with orthogonal injection has been also coupled to an MR-TOF MS with a folded ion path (see EP 1 237 044 A2 and J. Hoyes et al. in extended abstract ASMS 2000 `A high resolution Orthogonal TOF with selectable drift length` www.asms.org). The invention allows converting an existing commercial o-TOF into a dual reflecting instrument by introducing an additional short reflector between orthogonal source and detector. Energy of continuous ion beam controls number of ion reflections. The `folded path` MR-TOF MS retains full mass range and considerably improves resolution, but it also reduces duty cycle and geometrical efficiency of ion sampling into the orthogonal accelerator in addition to ion losses and scattering occurring at every pass through meshes in both ion mirrors.

The two above examples demonstrate that a conventional orthogonal acceleration becomes inefficient in MR-TOF MS, particularly at extended flight times. There have been multiple attempts of improving pulsed ion sampling from continuous ion beams, mostly employing ion storage in radio-frequency (RF) traps, like 3-D ion trap (IT) in the paper of B. M. Chien et al. `The design and performance of an ion trap storage-reflectron time-of-flight mass spectrometer` International Journal of Mass Spectrometry and Ion Processes 131 (1994) 149-119, linear ion trap (LIT) in U.S. Pat. No. 5,763,878, U.S. Pat. No. 5,847,386 (FIGS. 29-31), U.S. Pat. No. 6,111,250 (FIGS. 29-31), U.S. Pat. No. 6,545,268 and WO9930350 or dual LIT (GB2378312) and ring ion trap in paper of A. Luca et al., `On the combination of a linear field free trap with a time-of-flight mass spectrometer`, Rev. Sci. Instrum. V.72, #7 (2001), p 2900-2908. Since all of those solutions compromise temporal and/or spatial spread of ejected ion packets, the orthogonal injection is still the method of choice for singly reflecting TOF MS. Some trapping features are used in an intermediate scheme in U.S. Pat. No. 6,020,586, combining both an ion trapping step and an orthogonal acceleration. Slow ion packets are periodically ejected out of storing ion guide into a synchronized orthogonal accelerator. Compared to conventional o-TOF MS the scheme improves sensitivity, while moderately sacrificing resolution and mass range. The scheme has been coupled to coaxial MR-TOF MS in already described reference by M. Park. However, such instrument does not provide full mass range. It is still desirable to improve conversion of continuous ion beam into ion pulses fully suitable for TOF MS and particularly to multi-reflecting TOF MS.

Multiple reflecting TOF is also employed in tandem mass spectrometer in a co-pending application of one of the author (WO2004008481). A slow MR-TOF MS is used for slow separation of parent ions at a millisecond time scale and a short orthogonal TOF is used for fast mass analysis of fragments at a microsecond time scale. Fast collisional cell is used in-between to fragment ions without smearing time-of-flight separation in the MR-TOF MS. The scheme delivers a novel quality: it allows parallel or `multi-dimensional` MS-MS analysis, where fragment spectra are simultaneously acquired for multiple parents without mixing them. The scheme has a drawback that parent ions spread in the shift direction which strongly limits acceptance of analyzer and requires smaller divergence of ion beam coming out of the ion source. A higher acceptance of MR-TOF MS is desirable.

Summarizing the above, the MR-TOF MS of the prior art do not have spatial and time of-flight focusing to provide a certain retaining of ion beam along a substantially extended flight path. Most of references describe MR-TOF analyzer without considering their compatibility with ion sources as well as their utility in tandem mass spectrometers. In fact, a limited acceptance of the known MR-TOF analyzers seriously limits such coupling and is expected to cause ion losses at substantially elongated flight paths. Some references are made to actual coupling of MR-TOF MS to continuous ion sources, demonstrating strong improvement of resolution. However, resolution is gained at the expense of losing sensitivity and, in the case of coaxial reflections, of shrinking mass range. Therefore, there is a need for TOF mass spectrometer working with intrinsically continuous or quasi-continuous ion sources, and superior to o-TOF by a set of major analytical characteristics, namely--sensitivity, mass range and resolution. There is also a need for better schemes of coupling TOF MS into tandem mass spectrometers.

SUMMARY OF THE INVENTION

The inventors have realized that acceptance and resolution of MR-TOF MS with two-dimensional planar mirrors could be substantially increased by: (A) using a periodic set of lenses in a drift space, providing focusing in a shift direction; (B) employing a geometry of planar mirrors with at least 4 electrodes, which allows not only a known spatial ion focusing and a time-of-flight focusing with regards to energy, but also a novel time-of-flight focusing with regards to spatial spread.

The inventors further realized that an improved acceptance of the MR-TOF MS of the invention allows its efficient coupling to continuous ion sources via an ion storage device. Continuously arriving ions could be stored and pulse ejected out of a storing device, such as ion guide, IT, LIT or a ring ion trap thus saving ions between rare pulses of MR-TOF MS, sparse compared to o-TOF MS.

The MR-TOF MS of the invention provides an advantageous combination of ion optics features, compared to prior art, since: It has a full mass range, a property of a `folded path` scheme; It eliminates ion losses on meshes, since mirrors are gridless, It efficiently consumes continuous ion beams by storing ions in an ion trap with pulse ion ejection at lower frequency; It accepts wide ion beam produced by such traps, since the analyzer has a spatial focusing by periodic lens in a shift direction and spatial focusing by mirrors across the plane of the folded ion path; It improves resolution by providing a high-order time-of-flight focusing with respect to energy and, which is novel, to spatial spread of ion packets; It tolerates a larger turn-around time of ion packets by extension of the flight time, using folded path in multiple reflections of a well confined ion beam and as a result tolerates schemes with ion storing and pulsing out of various ion traps; The longer flight time brings another advantage--slower and less expensive detector and data acquisition system, both currently being very costly parts of TOF mass spectrometers.

The invention introduces a completely novel to MR-TOF MS feature--multiple lenses, optimally positioned in the middle of drift space, preferably with a period corresponding to ion shift per integer number of turns. Periodic lenses allow focusing of the beam and, thus, insure a stable confinement of ions along an extended folded ion path. The set of lenses brings the novel quality to MR-TOF: beam spatial and angular spreads stay limited even after an extremely large number of reflections (actually achieved if using reflections in the shift direction as well). Even more, using ion optics simulation the inventors found out that ion motion in the novel MR-TOF efficiently withstands various external distortions, like inaccuracy of geometry, stray electric and magnetic fields of pumps and gauges, as well as space charge of the ion beam itself. The MR-TOF returns ions into vicinity of main trajectory in spite of those distortions, similar to trapping in the potential grove. The feature of periodic lenses allows compact packaging of MR-TOF MS with an extended flight path, combined with a confident full transmission of ion beam.

The lens tuning allows periodic, repeatable focusing in a shift direction, achieved when focal length F matches an integer number of half reflections or quarters of full ion turns (P/4), F=N*P/4. The most tight focusing occurs when F=P/4. Such tight focusing is advantageous for minimizing shift per turn and making instrument compact. It is important that even under the condition of such tight focusing lenses remain weak because of a relatively long ion path per turn, and therefore they introduce only minor incorrigible time-of-flight aberrations with respect to the ion spatial spread in the plane of the folded ion path. Planar lenses, substantially elongated across the plain of ion path, provide an advantage of fairly independent tuning of spatial focusing by ion mirrors and by periodic lenses, since they focus in different directions. Besides, such lenses may also incorporate steering by using asymmetric voltages on side plates.

The invention allows further increase of the flight path length by employing reflections in a shift direction. Such reflections can be achieved, for example, by deflection plates, located on the sides of shift path in the middle of drift space between the mirrors. Deflection plates could operate constantly or in a pulsed mode to allow ion gating. A single reflection does not affect mass range, while a further increase of the flight path by multiple reflections in shift direction is achieved at the expense of mass range. The deflection plates could be also used to bypass the analyzer and to steer ions into a receiver.

Novel focusing properties of the mirrors of the invention are provided by choosing a proper distance between the mirrors and adjustment of electrode potentials. Such adjustment results in the 3rd-order time-of-flight focusing on ion energy, 2nd-order time-of-flight focusing with respect to the spatial ion spread across the plane of the folded ion path and spatial focusing across the said plane. The inventors realized that elimination of high-order time-of-flight aberrations is stable with respect to assembly defects as well as to moderate variations of the drift lengths and electrode potentials. Therefore, a high resolving power could be obtained by tuning of novel MR-TOF MS while adjusting only one electrode potential, in fact, varying one parameter--a linear dependence of the ion flight time on the ion energy.

The previously described focusing properties are realized, for example, in planar 4-electrode mirrors, composed of thick square frames, substantially elongated in a shift direction. The desired field structure also could be made using thin plates with slots, bars, cylinders, or curved electrodes. The edges of two-dimensional mirrors could be efficiently terminated using printed circuit boards to shorten the total physical length of the MR-TOF MS. Having more electrodes is very likely to further improve mirror parameters, but complicates the system.

In a preferred mode the ion source and the ion detector are located in the drift space between the mirrors. In such configuration the folded ion path remains far from mirror edges and the mirrors can be operated in a static mode to achieve better stability and mass accuracy of the MR-TOF MS. However, the invention is well compatible with a pulsed ion admission from external source or ion release through ion mirrors in order to couple the MR-TOF MS with external ion sources or ion receivers and to avoid beam passage through fringing fields of mirror edges.

The invention is applicable to various ion sources, including pulsed ion sources, like MAIDI or SIMS, quasi- continuous ion sources, like MALDI with collisional cooling, as well as intrinsically continuous ion sources like ESI, EI, CI, PI, ICP or a fragmenting cell of a tandem mass spectrometer. All continuous or quasi-continuous ion sources preferably operate with an ion guide.

As mentioned earlier, having a much wider acceptance, the MR-TOF MS of the invention can be used in conjunction with an ion storing device, avoiding ion losses between infrequent accelerating pulses. Such ion storing can occur in gas filled radio frequency (RF) storing devices of various kinds, including ion guides, RF channels, ring electrode traps, wire guides, IT or LIT, incorporated either into an ion source itself or into an accelerator of the MR-TOF MS. The invention employs either: a direct acceleration out of an ion storing device, axial or orthogonal, or a dual acceleration scheme, where slow ion pulse is ejected out of the storing device with consecutive pulsed acceleration, axial or orthogonal, such accelerator may be made either as a DC accelerator or an RF ion guide switching between RF transmitting mode and DC pulsing mode, or a dual storage scheme, where slow ion pulses are released from a first storing trap and admitted into the second trap usually operated at a lower gas pressure. Ion ejection out of the second storing device can be also made axially or orthogonally, or via an additional accelerator, axial or an orthogonal.

Some compromises in parameters of ion packets are acceptable because of substantial extension of flight path and wide acceptance of the novel MR-TOF MS.

The preferred embodiment of the invention employs the latter- more complex, but advantageous scheme of dual ion storage. Ion guides are preferred choice for both storage devices. It is preferable using an additional set of pulsed electrodes, whose field well penetrates into ion storage area of the second ion guide and allows fast ion ejection in axial direction with a small turn around time, while providing fairly uniform accelerating field and a moderate ion divergence. Compared to orthogonal acceleration scheme the invention provides an almost complete utilization of continuous ion beam. Some increase of the turn around time is compensated by an extension of the flight path.

The invention suggests several novel ion storing devices, such as a hybrid ion trap, composed of ion guide and a 3-D ion trap with an open ring electrode. Simulations of the segmented analog have shown feasibility of such trap for preparation of ions for MR-TOF analysis. Another novel device comprises a linear ion trap with auxiliary electrodes. Both ion trapping and axial ejection could be achieved by pulsing voltages on separate set of electrodes, and not having any RF signals on them.

The invention is expected to provide more intense ion pulses and as a result dynamic range and life time of the ion detector become an important issue. Multiple solutions are known in the art, including ion suppression either at ion storage, or mass separation or detection stages. The known strategies include automatic adjustment of ion intensity or mass filtering of unwanted beam components. Dynamic range is enhanced by using a secondary electron multiplier (SEM) and analog to digital converters (ADC) for data acquisition. A specific of the invention is in longer pulse duration, allowing lower bandwidth and somewhat easier solutions of the above problems.

The scheme is expected to provide a complete utilization of continuous or quasi-continuous ion beam as well as an improved resolution, in the range of R.about.100,000. The MR-TOF MS could be used either as a stand-alone instrument, or as a part of LC-MS or MS-MS tandem, first of all expected as a second analyzer of fragment ions, combined with any know mass separator of parent ions and a with any known kind of fragmenting cell.

The MR-TOF MS of the invention could be also used as a first, separating mass spectrometer in a tandem mass spectrometer arrangement. The advantage of using MR-TOF becomes apparent in a co-pending patent by one of the authors. The co-pending invention suggests using slow TOF1 for ion separation, combined with a fast TOF2 for fragment analysis. The arrangement allows parallel analysis of multiple precursors per single pulse out of ion source. Current invention allows particularly long separation in MR-TOF MS, as well as separation at low and medium energy of ion beam, tight focusing of the beam and precise control of ion beam location, useful while directing the beam into a fragmenting cell.

An enhanced transmission and enhanced resolution of MR-TOF could be also used in both stages of mass spectrometric analysis. In this case a prolonged flight time in the second shoulder requires selection of a single precursor by a timed ion selector, thus loosing opportunity of parallel MS-MS analysis, but instead providing for high specificity, resolution and mass accuracy of MS-MS analysis. Multi-stage MSn analysis could be accomplished in an instrument with a single MR-TOF analyzer. For example, the same analyzer could be used both for parent separation, daughter separation and grand-daughter ion analysis if the collisional cell reverts direction of ion flow and timed ion selector is used between MR-TOF and fragmentation cell. Ions are passed between MR TOF analyzer and collisional cell back and forth.

Both modes of parallel MS-MS analysis and of high resolution MS-MS analysis could be accomplished in a single versatile instrument by adjusting flight path and acceleration voltage, preferably on both MR-TOF. Reducing voltage in a first analyzer and reducing flight path (by pulse deflecting ion beam and using fewer reflections) in the second analyzer would provide such versatility.

Ceriainly, the utility of MR-TOF MS of the invention spreads onto a much wider variety of devices and methods. As an example, MR-TOF MS could be combined with any up-front sample separation in various types of chromatography, or mass spectrometric separation in any type of external mass spectrometer or ion mobility spectrometer. A variety of gas filled storage devices and gas filled fragmentation cells employed in various embodiments could be as well converted into gaseous ion reactors. Such reactors could be useful for example for employing ion-molecular reactions in ICP method to enhancing isotopic sensitivity, could be using ion-ion reactions between multiply charged ions and ions of the opposite polarity, either for charge reduction or selective fragmentation, so as such reactors could be used for electron capture dissociation of multiply charge ions.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the present invention, reference is now made to the following drawings in which:

FIG. 1 shows a multi-reflecting time-of-flight mass spectrometer (MR-TOF MS) of prior art, by Wollnik et al, GB patent No 2080021 (FIG. 3 and FIG. 4 of the GB patent).

FIG. 2 shows a `folded path` MR-TOF MS of a prototype by Nazarenko et al., SU1725289.

FIG. 3 shows a `coaxial reflecting` MR-TOF MS of prior art by M. Park, U.S. Pat. No. 6,107,625.

FIG. 4 shows a schematic of the preferred embodiment of the MR-TOF MS of the invention, with details on novel periodic lenses.

FIG. 5 shows MR TOF analyzer geometry and potentials of ion mirrors of the preferred embodiment of the invention.

FIG. 6 shows a schematic and principles of ion path extension by edge ion reflections in the shift direction.

FIG. 7 shows a generalized schematic of ion sampling from continuous ion sources into the MR-TOF MS of the invention using an intermediate ion storage device, wherein:

FIG. 7A shows a block diagram of the pulsed ion source in the MR-TOF MS;

FIG. 7B shows details of the electrospray ion source as an example of the continuous ion source;

FIG. 7C shows details of the MALDI ion source with collisional dampening as an example of the quasi-continuous ion source;

FIG. 7D shows details of the intermediate storage ion guide;

FIG; 8 shows a schematic of a second ion storage device and of the ion accelerator;

FIG. 9 shows a block diagram of dual ion storage with axial ejection and with an optional accelerator;

FIG. 10 shows a particular arrangement of a second storage device providing a pulsed axial ion ejection.

FIG. 11 shows an arrangement with orthogonal acceleration out of non-storing ion guide

FIG. 12 shows a particular arrangement of the second storage device forming a hybrid of a quadrupole ion guide and 3-D quadrupole ion trap.

FIG. 13 shows a segmented analog of the hybrid trap.

FIG. 14 shows the detailed schematics of the preferred embodiment of MR-TOF MS of the invention.

FIG. 15 shows the schematics of the preferred embodiment of tandem mass spectrometer with parallel MS-MS analysis and including MR-TOF MS as a first MS stage of slow separation of parent ions.

FIG. 16 shows the schematics of the preferred embodiment of tandem mass spectrometer with MR-TOF MS at both MS stages providing a versatile switching between high throughput and high-resolution modes of MS-MS analysis.

FIG. 17 shows the preferred embodiment of mass spectrometer for multistage MSn analysis, and employing a single MR-TOF MS analyzer and a fragmentation cell, reverting ion flow.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention relates generally to the area of mass-spectroscopic analysis, and more particularly is concerned with the apparatus, including a multi reflecting time-of-flight mass spectrometer (MR TOF MS). More specifically, the invention improves resolution and sensitivity of planar and gridless MR-TOF MS by employing a novel arrangement and control of mirror electrodes in combination with a periodic set of lenses in a drift space. Because of improved spatial and time focusing, the MR-TOF MS of the invention has a wider acceptance and confident confinement of ion beam along an extended folded ion path. As a result, the MR-TOF MS of the invention can be efficiently coupled to continuous ion sources via an ion storage device, thus saving on duty cycle of ion sampling. The MR-TOF MS of the invention is suggested for use in tandem mass spectrometers, either as a first slow separator in tandems with two-dimensional parallel MS-MS analysis or as a tandem employing MR-TOF MS at both stages of analysis.

FIG. 1 shows a multi-reflecting time-of-flight mass spectrometer (MR-TOF MS) of prior art, by Wollnik et al., GB patent No 2080021 (FIG. 3 and FIG. 4 of the GB patent). In a time-of-flight mass spectrometer ions of different masses and energies are emitted by a source 12. The flight path of ions to a collector 20 is folded by arranging for multiple reflections of the ions by mirrors R1, R2, . . . Rn. The mirrors are such that the ion flight time is independent of ion energy. The patent shows two geometrical arrangements of multiple axially symmetric ion mirrors. In both arrangements ion mirrors are located in two parallel planes I and II and are aligned along the surface of ion path. In one arrangement this surface is a plane and in another one it is a cylinder. Note that ions travel at an angle to optical axis of ion mirrors which induces additional time-of-flight aberrations and thus considerably complicates achieving high resolution.

FIG. 2 shows a `folded path` MR-TOF MS of a prototype by Nazarenko et al., described in Russian patent SU1725289. The MR-TOF MS of the patent comprises two gridless electrostatic mirrors, each composed of three electrodes 3, 4 and 5 for one mirror, and 6, 7 and 8 for another mirror. Each electrode is made of a pair of parallel plates `a` and `b`, symmetric with respect to the `central` plane XZ. A source 1 and receiver 2 are located in the drift space between the said ion mirrors. The mirrors provide multiple ion reflections. Number of reflections is adjusted by moving the ion source along the X-axis relative to the detector. The patent describes a type of ion focusing which is achieved on every ion turn, achieving a spatial ion focusing in Y direction and a second order time of flight focusing with respect to ion energy.

Note that the prototype provides no ion focusing in the shift direction, thus essentially limiting the number of reflection cycles. It also does not provide time-of-flight focusing with respect to spatial ion spread in Y direction. Therefore, the MR-TOF MS of the prototype fails delivering wide acceptance of analyzer and thus an ability of working with real ion sources. Finally, the prototype has no implication on the type of ion source, and on efficient ways of coupling of MR-TOF MS to various ion sources.

FIG. 3 shows a `coaxial reflecting` MR-TOF MS of prior art by M. Park, U.S. Pat. No. 6,107,625. The invention comprises two electrostatic reflectors 34 and 38, positioned coaxially with respect to one another such that ions generated by an ion source 32 can be reflected back and forth between reflectors. The first reflecting device 34 combines functions of an orthogonal accelerator and of an ion mirror. After multiple ion reflections either of mirrors is rapidly switched off to allow the ions to pass through the reflector and onto an ion detector 36. The patent teaches a way of coupling of continuous ion source to an MR-TOF MS. The described apparatus indeed achieves high resolution within a small size instrument. However, an employed `coaxial reflecting` scheme strongly reduces mass range and decreases the duty cycle of ion sampling from a continuous ion beam. Meshes cause substantial ion losses. Duty cycle is improved in a later work by author after introducing a storing linear ion trap (LIT) into the ion source.

FIG. 4 shows a schematic of the preferred embodiment of the MR-TOF MS of the invention, with details on novel periodic lenses. The MR-TOF MS 11 comprises a pulsed ion source 12 with a built in accelerator 13, an ion receiver 16, a set of two gridless ion mirrors 15, parallel to each other and substantially elongated in a `shift` direction, denoted here as Y axis, a field-free space 14 between the said mirrors and a set of multiple lenses 17, positioned in the said drift space.

The above elements are arranged to provide a folded ion path 19 between the ion source 12 and the ion receiver 16, the said ion path being combined of multiple reflections between the ion mirrors 15 and of an ion drift in the shift Y direction. The shift is arranged by slight tilting, mechanically or electronically, of the incoming ion packets with respect to the X-axis. The lenses 17 are positioned along the Y-axis with a period corresponding to ion shift per integer number of ion reflections. The preferred embodiment strongly enhances acceptance of the MR-TOF MS by providing novel ion optics properties--periodic focusing by lenses 17 in the shift Y direction, complementing a periodic spatial focusing in the orthogonal Z direction, provided by planar gridless ion mirrors. Those ion optics properties as well as improved time-of-flight focusing by specially designed ion mirrors of the invention are discussed below in more details.

Incorporation of periodic lenses is a completely novel feature in MR-TOF MS, which provides stable retention of the ions along the main jigsaw folded ion path. The lens tuning allows periodic, repeatable focusing in a shift direction, achieved when focal length F matches an integer number of half reflections or quarters of full ion turns (P/4), F=N*P/4. The tightest focusing occurs when F=P/4. Such tight focusing is advantageous for minimizing shift per turn and making instrument compact. It is important that even under the condition of such tight focusing lenses remain weak because of a relatively long ion path per turn, and therefore they introduce only minor incorrigible time-of-flight aberrations with respect to the ion spatial spread in the plane of the folded ion path. Preferably lenses are lenses, i.e. substantially elongated across the plain of ion path, to provide an advantage of fairly independent tuning of spatial focusing by ion mirrors and lenses across the plane of the folded ion path a