DE69806415T2 - METHOD FOR THE EXAMINATION OF IONS IN AN APPARATUS WITH A FLIGHT-TIME SPECTROMETER AND A LINEAR QUADRUPOL ION TRAP - Google Patents

Description

Field of the invention

This invention relates to mass spectrometry and, more particularly, to a method of analyzing ions in an apparatus comprising a time-of-flight mass spectrometer.

Background of the invention

In the field of mass spectrometry, a large number of different spectrometers have been developed, as well as combinations of different spectrometer elements. A commonly known type of spectrometer is a four-pole mass spectrometer, and it is known to provide devices with two or more mass-analyzing four-pole stages for MS/MS capabilities. It is also known to combine a four-pole stage with a time-of-flight mass spectrometer (TOF-MS), as detailed below. A TOF-MS has the advantages of high scan speed, unlimited mass range, and, when a reflectron is used, a resolution of 10,000 or more. However, a TOF-MS does not typically provide MS/MS capabilities. 3D ion trap mass spectrometers can perform MS/MS analysis in a relatively simple device, but generally operate at a lower resolution than a reflectron TOF MS. Higher resolution can be achieved with an ion trap mass spectrometer, but only at very low scan speeds. Furthermore, it is also difficult to feed ions from an external source into a 3D ion trap, and the mass range is also limited.

A proposal by one of the inventors of the present invention is disclosed in US Patent No. 5,179,278. This patent describes the use of an RF multipole ion guide as an interface between an ion source and an ion trap. The intention is to improve the duty cycle of the ion trap mass spectrometer. However, there are no specific teachings on the use of the Multipole device itself in a full trap mode to provide MS/MS capabilities. Rather, the teaching is that trapping is achieved by applying selected electrical potentials to the ends of the space in the multipole device to cause the ions to reflect from a second outlet end to a first inlet end and then back to the second outlet end. This retains the ions in the space for an extended period of time, long enough to perform analysis on an ion sample previously introduced into the ion trap spectrometer.

US Patent No. 5,652,427 describes the use of an RF multipole which includes a number of separate stages of varying vacuum. This arrangement is intended to simply transfer ions from a high pressure source to the mass spectrometer. There is no teaching of ion trapping in a multipole stage; nor is there any teaching of MS/MS capabilities by resonance excitation and ejection and the like.

U.S. Patent No. 5,420,425 (Bier et al., issued to Finnigan Corporation) relates to an ion trap mass spectrometer for the analysis of ions. It includes electrodes having a shape such that they promote an increased volume occupied by ions. A four-pole field is provided to trap the ions within a predetermined range of mass-to-charge ratios, then the field is changed so that the trapped ions with the specific masses become unstable and exit the trap chamber in a direction orthogonal to the central axis of the chamber. The ions exiting the spectrometer are detected to provide a signal indicative of their mass-to-charge ratios. The patent teaches a method in which ions within a predetermined range of mass-to-charge ratios are first fed into the chamber and then the field is changed to select only some of the ions for further manipulation. The four-pole field is then adjusted so that it is able to capture product ions from the remaining ions. The remaining ions are then dissociated or a neutral gas to form these product ions. The quadrupole field is then changed again to remove ions whose mass-to-charge ratios are within the desired range for detection. It should be noted that the ions are not detected by a time-of-flight (TOF) instrument. The Finnigan device produces an ion stream with a broad spatial and velocity distribution because it uses radial ejection. It would be difficult to handle such a beam and introduce it into a TOF-MS analyzer.

Others have shown how to interface a TOF-MS with an electrospray source using a linear RF quadrupole operating at a moderately high pressure (e.g., Chernushevich et al., presented at the 44th ASM Conference on Mass Spectrometry and Allied Topics, Portland, Oregon, May 12-16, 1996). Others have used six-pole and eight-pole ion guides instead of a quadrupole. In six-pole and eight-pole fields, ions with different m/z typically do not have generally defined frequencies of motion, and thus resonance excitation or ejection of selected ions is not possible, which is a significant advantage of using a quadrupole.

It is also known to use a 3D ion trap as an interface between an ion source and a TOF-MS (S. M. Michael et al., Rev. Sci. Instr. 63, 4277-4284 (1992); Purves and Li, J. Microcolumn Separations 7 (6), 603, (1995)). The 3D ion trap can be provided with MS/MS capability (Qian and Lubman, Rap. Commun. Mass. Spec. 10, 1079 (1996)). The use of a three-dimensional ion trap has a number of disadvantages. For example, the efficiency of ion injection is at least 10 times lower than the efficiency with a two-dimensional quadrupole. Second, the ion storage volume in the three-dimensional trap is smaller, so that only a relatively small number of ions can be stored without causing space charge problems, and for this reason the dynamic concentration range in a three-dimensional trap is limited.

A related approach has been proposed using two separate multipoles and then a TOF mass spectrometer (H. R. Morris et al., Rap. Commun. Mass. Spec. 10, 889 (1996)). Here, the selection of ions at a given m/z is conventionally performed in a first four-pole mass filter. These are then sent to an RF six-pole and dissociated by collision with a neutral gas. The resulting ions then travel to a TOF MS to obtain a spectrum of the product ions. In addition, a system with a first mass analysis four-pole and a second RF four-pole has been described (Chevchenko, Rapid Communications in Mass Spectrometry, Vol. 11, 1015-1024 (1997)). Both systems are relatively complex and cost-intensive and have a number of stages, which are likely to lead to a loss of sensitivity.

Finally, a more recent proposal was found in a paper entitled "A New Technique for Decomposition of Selected ions in Molecule Ion Reactor Coupled with Ortho-Time-of-Flight Mass Spectrometry" (A. Dodonov et al., Rapid Communications in Mass Spectrometry 11, 1649-1656 (1997). This paper shows limited experimental results performed on preselected ions, i.e., the tests were carried out on a single chemical compound. There is no specific teaching regarding the use of the device for performing the selection stage. Two modes of ion dissociation are disclosed. In a first mode, the motion of the parent and fragment ions is chosen to be stable, and the RF electric field forces the ions to oscillate about the quadrupole axis. At the same time, a DC potential is applied along the axis of the device to accelerate the ions, and the strength of this field regulates the collision-induced fragmentation of the ions. The quadrupole is filled with gas which has a pressure of about 1 mbar for this purpose. There is no ion mass for the charge ratio selection and all ions present are accelerated by this field. Fragment ions with mass-to-charge ratios above or below the m/z value of a parent ion can be transferred to a TOF mass analyzer for analysis. It should be noted that the applied field also causes acceleration and possible further fragmentation of the fragment ions, although regulation of the field strength can limit this to some extent. Nevertheless, the applied axial field does not discriminate between the different ion types.

In a second mode, ions are fragmented by confining them in the quadrupole with the RF electric field selected to have such an amplitude and frequency that the desired ions are close to the limit for stable ion motion with the Mathieu parameter q = 0.9. This causes an increase in the output ion velocity and thus leads to a "heating" and fragmentation of the output ions by collision. Thereafter, only those ions are stable in the quadrupole whose m/z ratios are higher than those of the predecessor or output ions, and only these ions are transmitted to the detector, i.e. the TOF-MS. Ions with an m/z ratio lower than that of the output ion are deflected due to the unstable nature of their motion. This may not be a significant limitation for multiply charged ions, since some fragment ions have lower charges and thus higher mass-to-charge ratios, but for singly charged ions no fragments are detected.

A disadvantage of both modes is that all ions in the quadrupole are excited and dissociate at the same time. If two compounds are present, both would fragment and in general it would not be possible to identify which fragments come from which precursor.

US Patent No. 5,576,540 (Jolliffe) discloses a unique radial ejection mass spectrometer. One of the rods of a conventional four-pole rod set is provided with a slot, and aligned with the slot is an "ion tube" which directs ejected ions to a detector. The ion tube consists essentially of a number of rod sets configured approximately as adjacent quadrupole rod sets to direct the ions to the detector. Now the assumption is that a final mass analysis step is performed by scanning the ions sequentially from the quadrupole rod set through the slot in one of the rods to the detector. In other words, there is no assumption that this quadrupole rod configuration is combined with another complete mass analyzer section, such as a time-of-flight mass analyzer.

US Patent No. 5,689,111 is also interesting. It discloses a time-of-flight mass spectrometer with a linear, two-dimensional ion guide that couples an ion source to the inlet of the time-of-flight instrument. The two-dimensional ion guide can be used as an ion storage device to improve the duty cycle of the time-of-flight instrument.

Summary of the invention

The present inventors have realized that it is possible to obtain the capabilities of a tandem mass spectrometer in a relatively simple device by connecting a linear quadrupole or other multipole to a TOF-MS. The quadrupole or other multipole is operated as an ion trap, and an ion is selected by the resonant ejection of ions of other masses or otherwise. The isolated ions are then excited and allowed to collide to undergo dissociation or fragmentation in the quadrupole or multipole.

In accordance with the present invention there is provided a method of analyzing ions in a mass spectrometer apparatus comprising an ion source, a linear RF quadrupole and a time-of-flight mass spectrometer, the method comprising the steps of:

(1) generating ions from the ion source and directing the ions into the linear RF quadrupole;

(2) applying potentials to the respective ends of the linear RF four-pole and operating the linear RF four-pole as an ion trap;

(3) selecting ions of interest in the linear RF quadrupole and ejecting unwanted ions; characterized in that the method comprises:

(4) exciting the ions and colliding them with a neutral gas to cause their collision-induced dissociation, thereby forming fragment ions for analysis in the time-of-flight mass spectrometer;

(5) adjusting the potential at one end of the linear RF quadrupole to pass the selected and fragment ions through the time-of-flight mass spectrometer; and

(6) obtaining a spectrum of the selected and fragment ions in the time-of-flight mass spectrometer.

A four-pole device is preferably used as they inherently have well-defined stability parameters and frequencies of excitation for a given ion. The x and y motions are separate and can be excited with good selectivity. However, for some applications it may be desirable or possible to use other 2D multipole designs, such as a six-pole or eight-pole. If such an instrument is operated at low RF voltages, the ion motion is likely to be a harmonic motion with well-defined frequencies (as described by Gerlich in Advances in Chemical Physics, Vol. 82, 1-176 (1992)). It should also be noted that the linear RF four-pole or multipole may comprise a single four-pole or multipole, or alternatively two sets of four-pole or multipole rods may be provided in tandem.

Another aspect of the present invention is that the linear RF quadrupole can be used to perform numerous mass spectrometry steps to perform, for example, Msn. Thus, after step (4), the method may comprise an additional step of isolating and exciting one or more fragment ions in the linear RF quadrupole to cause collision-induced dissociation of one or more of the fragment ions, thereby forming further fragment ions. Further, the method may comprise numerous cycles of isolating and exciting one or more of the fragment ions in the linear RF quadrupole, each cycle comprising isolating and exciting at least one or more fragment ions formed in the previous cycle to form further fragment ions. In each cycle, all of the fragment and selected ions may be excited to thereby cause collision-induced dissociation.

The selected ions and/or the fragment ions may be excited by (i) exciting the selected ions by resonant excitation at a particular secular frequency and (ii) applying a broadband excitation waveform to cause collision-induced dissociation of the selected ions.

Another aspect of the invention provides an apparatus comprising one or more linear RF quadrupoles or other multipoles and a time-of-flight mass spectrometer, the apparatus being adapted to perform the method of the present invention.

Short description of the drawing

For a better understanding of the invention and to show more particularly how the invention may be carried into effect, reference will now be made, by way of example, to the accompanying drawing which illustrates schematically a preferred embodiment of the present invention.

Detailed description of the preferred embodiment Referring to the drawing, an electrospray source is designated 2. It should be noted that any suitable ion source may be used, such as El (electron ionization), Cl (chemical ionization), laser desorption, etc. Ions from the source 2 migrate through an orifice 4. A supply of nitrogen gas, which may be heated, is provided as indicated to promote evaporation of the solvent. The ions then migrate into a chamber 5 which is equipped with a connection to a rotary pump to maintain a desired low pressure. A skimmer 6 then provides an orifice through which the desired ions migrate into a first RF quadrupole 8. As already known, this comprises a quadrupole rod set which is equipped with the usual connection for the supply of RF and DC voltages. The quadrupole 8 is operated in RF mode only to transfer ions of a wide range of mass to charge ratios. For simplicity, details of electrical connections and electrical supplies have been omitted.

An input lens 10 separates the first quadrupole 8 from a second RF quadrupole 12, but it should be noted that the lens 10 does not separate two chambers, since the two quadrupoles 8, 12 are essentially in a single chamber, although two chambers could be used at different pressures. The second quadrupole 12 is also used only in RF mode. As illustrated at 11, a connection to a turbo pump is provided to maintain a pressure of about 1-10 millitorr. For example, the first quadrupole 8 may be 5 cm long and the second quadrupole 12 may be 20 cm long, i.e. the quadrupoles do not have to be the same length.

At the exit from the second quadrupole 12 there is an exit aperture 14 and thereafter a series of additional lenses or electrodes 16 to steer the ion beam and ensure that it penetrates into a source region 18 of a time-of-flight mass spectrometer (TOF-MS) 20.

Here, the time-of-flight mass spectrometer 20 is shown orthogonal to the axis of the quadrupoles 8, 12. Note that the TOF-MS 20 could also be arranged axially with respect to the quadrupoles 8, 12. In a known manner, a connection 22 is provided to allow the TOF-MS to be pumped down to a desired vacuum level.

If potentials of the inputs and outputs of the quadrupoles 8, 12 are set so that they continuously transfer ions in use, the conventional operation of the TOF-MS 20 results in a mass spectrum of ions from the source 2. As is known, the electrodes in the source region 18 of the TOF-MS 20 are activated to collect and provide the pulses of ions migrating through the TOF-MS, measuring their time of flight to obtain a spectrum for these ions.

In accordance with the present invention, retarding potentials can now be applied to the output and input of one or both of the first and second quadrupoles 8, 12. This serves to trap ions in the respective quadrupole. Undesired trapped ions can then be ejected by resonant excitation at secular frequencies of the ions. Also, ions of a single m/z value can be trapped and ejected by ejecting all other ions with a filtered noise field or SWIFT waveform as is already known, which is essentially a noise waveform having a dip or gap at the frequency corresponding to the secular frequency of the ion of interest. The isolated ions can then be excited and dissociated by collision with a neutral gas. There are a variety of ways in which excitation, collision or fragmentation can be triggered. Thereafter, the resulting ion fragments can be driven or transferred into the TOF-MS 20 by lowering the trapping voltage on the electrode 14 between the second quadrupole 12 and the TOF-MS 20. The ions enter the source region of the TOF-MS 20 and the mass spectrum of the fragment ions can be obtained.

The ions may be allowed to enter the source region 18 of the TOF-MS with near thermal energies, which they may have received from the second quadrupole 12. Alternatively, they may be accelerated toward the source region 18 by establishing an appropriate axial field in the second RF quadrupole 12 (as described by B. Thomson et al., at the 44th ASM Conference on Mass Spectrometry and Allied Topics, May 12-16, 1996, Portland, Oregon). Thermal ions typically take on the order of tens of milliseconds to migrate to the source region of the TOF-MS, and accelerating the ions into the TOF-MS 20 has the advantage of reducing the transmission time to about 1 ms.

Thus, for example, in ICP-MS, intense AR+ ions can cause difficulties and effectively paralyze the detector. To overcome this problem, an ion sample can be fed from a source 2 into the first quadrupole 8. There, potentials can be applied to the skimmer 6 and lens 10, as well as a field applied at the resonant frequency of the AR+ ions to effectively eject them from the ion sample. The voltage of lens 10 can then be adjusted to direct the ion sample into the second quadrupole. There, a filtered noise field or SWIFT waveform could be provided to further isolate an ion of interest. The voltage at aperture 14 and lens 16 is then adjusted so that the desired ion is directed into TOF-MS 20.

Claims (12)

1. A method for analyzing ions in a mass spectrometer device comprising an ion source (2), a linear RF multipole (12) and a time-of-flight mass spectrometer (20), the method comprising the steps of: (1) generating ions from the ion source (2) and directing the ions into the linear RF multipole (12); (2) applying potentials to respective ends of the linear RF multipole (12) and operating the linear RF multipole (12) as an ion trap; (3) selecting ions of interest in the linear RF multipole (12) and rejecting unwanted ions; characterized in that the method comprises: (4) exciting the selected ions and colliding the ions with a neutral gas to cause their collision-induced dissociation, thereby forming fragment ions for analysis in the time-of-flight mass spectrometer (20); (5) adjusting the potential at one end of the linear RF multipole (10) to pass the selected and fragment ions through the time-of-flight mass spectrometer (20); and (6) obtaining a spectrum of the selected and fragment ions in the time-of-flight mass spectrometer (20). 2. The method of claim 1, wherein step (3) comprises ejecting ions at a predetermined secular frequency by exciting at the secular frequency. 3. The method of claim 1, wherein step (3) comprises applying a filtered noise field to eject ions other than a desired ion having a single m/z value or ions having a range of m/z values. 4. A method according to claim 1, 2 or 3, comprising after step (4) an additional step of exciting one or more fragment ions in the linear RF multipole (12) to cause collision-induced dissociation of one or more of the fragment ions to form further fragment ions. 5. The method of claim 4 comprising multiple cycles of exciting one or more of the fragment ions in the linear RF multipole (12), wherein each cycle comprises exciting one or more of the fragment ions formed in the previous cycle to form further fragment ions. 6. The method of claim 5, wherein in each cycle all of the fragment and the selected ions are excited to cause collision-induced dissociation. 7. A method according to any preceding claim, which comprises exciting the selected ions by resonance excitation at a certain secular frequency. 8. A method according to any one of claims 1 to 6, comprising applying a broadband excitation waveform to cause collision-induced dissociation of the selected ions. 9. The method of claim 5, comprising exciting the selected ions and one or more of the fragment ions by exciting the selected and fragment ions by resonance excitation at certain secular frequencies. 10. The method of claim 5, comprising exciting the selected ions and one or more of the fragment ions by applying a broadband excitation waveform to cause collisionally induced dissociation of the selected and fragment ions. 11. Method according to one of the preceding claims, which comprises carrying out the method using one of a hexapole and an octopole rod set as a linear RF multipole (12). 12. Method according to one of claims 1 to 10, which comprises carrying out the method using a quadrupole rod set as a linear RF multipole (12).