WO2019211918A1 - Orthogonal acceleration time-of-flight mass spectrometer - Google Patents

Abstract

According to the present invention, when a user specifies, via an input unit (54), a mass range of a mass spectrum desired for observation, a CES analysis control unit (51) controls respective components so that MS/MS analysis is conducted while sequentially varying collision energy to a plurality of predetermined values. Here, a delay time from the time at which ions are discharged from a collision cell (13) until the time at which the ions are accelerated by an orthogonal accelerator (17) is determined in accordance with the mass range. In the interior space of an ion guide (14), a gradient of the depth of a potential is formed in the direction of ion travel, thereby enabling achieving of a high ion accumulation effect over a broad m/z range. The upper limit of this m/z range is dependent on the delay time, and therefore, by determining the delay time according to the mass range, it is possible to reliably achieve a high detection sensitivity within the m/z range of that particular mass range. As a result, it becomes possible to produce a preferable mass spectrum that enables observation of a variety of product ions generated from dissociation under different collision energies.

Description

Orthogonal acceleration time-of-flight mass spectrometer

The present invention relates to an orthogonal acceleration type time-of-flight mass spectrometer, and more specifically, to a quadrupole-time-of-flight mass spectrometer that conducts mass analysis by introducing ions dissociated by a collision cell into an orthogonal acceleration type TOFMS. The present invention relates to a suitable orthogonal acceleration time-of-flight mass spectrometer.

MS / MS analysis (tandem analysis), which is a method of mass spectrometry, is a useful method for identifying compounds with large molecular weights and analyzing their compound structures, and has been widely used in various fields in recent years. Yes. As a mass spectrometer capable of MS / MS analysis, a triple quadrupole mass spectrometer and a quadrupole-time-of-flight mass spectrometer (hereinafter referred to as “Q-TOF mass spectrometer”) are well known. ing.

The triple quadrupole mass spectrometer is a device in which a quadrupole mass filter is arranged before and after a collision cell that dissociates ions by collision-induced dissociation (CID). In this triple quadrupole mass spectrometer, ions having a specific mass-to-charge ratio m / z are selected by a preceding quadrupole mass filter from various ions derived from sample components generated in an ion source. Then, the selected ions are dissociated as precursor ions by a collision cell, and various product ions generated by the dissociation are separated and detected by a quadrupole mass filter in the subsequent stage according to the mass-to-charge ratio. On the other hand, the Q-TOF mass spectrometer can be simply described as follows. The quadrupole mass filter in the latter stage of the triple quadrupole mass spectrometer is a time-of-flight mass spectrometer (hereinafter referred to as “OA-” as appropriate). In general, a mass spectrum can be obtained with higher resolution and mass accuracy than a triple quadrupole mass spectrometer.

Since the binding energies of various binding sites in the compound differ from site to site, the ease of cleavage also varies from site to site. Therefore, in a triple quadrupole mass spectrometer or a Q-TOF mass spectrometer, for example, a direct current bias voltage applied to the previous quadrupole mass filter and a direct current applied to an ion guide disposed in the collision cell. It is known that when the collision energy determined by the voltage difference from the bias voltage is changed, even in the same precursor ion derived from the same compound, the dissociation mode is different and the peak pattern of the obtained mass spectrum (product ion spectrum) is different. Yes.

Generally, in order to identify or analyze a compound having a complex structure, it is more convenient to know the masses of various fragments (product ions and neutral loss) derived from the compound. Therefore, it is possible to observe more types of product ions by repeating mass analysis of product ions while changing the collision energy in multiple steps for one target compound, and integrating multiple mass spectra obtained in this way. A method of creating a mass spectrum to be generated (hereinafter, this method is referred to as a CES (collision energy spread) method) is known (see Patent Document 1 and the like). That is, the mass spectrum created in this way is a mass spectrum in which peaks derived from various product ions generated by dissociation under different collision energies are mixed.

Although the quadrupole mass filter is not so high in mass resolution, a mass spectrum over a relatively wide mass-to-charge ratio range can be obtained by scanning measurement. Therefore, when implementing the CES method in a triple quadrupole mass spectrometer, the mass-to-charge ratio range of the scan measurement with the quadrupole mass filter at the subsequent stage should be kept constant with respect to different collision energies at a plurality of stages. Can do.

In contrast, in OA-TOFMS used in a Q-TOF type mass spectrometer, in general, the mass-to-charge ratio range of the mass spectrum obtained by one measurement is considerably limited. This is because in OA-TOFMS, the ion flow introduced into the orthogonal acceleration part is accelerated in a pulsed manner in a direction substantially orthogonal to the traveling direction and sent to the flight space. When acceleration voltage is applied, orthogonal acceleration is performed. This is because only ions passing through the part are to be measured.

For example, in the Q-TOF type mass spectrometer described in Patent Document 2, ions to be measured are temporarily accumulated in the collision cell, and the accumulated ions are discharged from the collision cell and the compressed ion flow is interrupted. In general, a configuration is adopted in which ions are fed into the orthogonal acceleration unit and ions are accelerated in the orthogonal acceleration unit in accordance with the timing when the ion flow is supplied. Although the mass-to-charge ratio range of ions to be measured in one measurement is expanded by such a method, the mass-to-charge ratio range is narrower than that of a quadrupole mass filter.

Therefore, when the CES method is realized in a Q-TOF mass spectrometer, an appropriate setting of the mass-to-charge ratio range of the measurement object in Q-TOFMS for different collision energies at a plurality of stages is high in a wide mass-to-charge ratio range. This is important in creating a mass spectrum of detection sensitivity. In particular, in the CES method, depending on the relationship between the type of compound and the collision energy, the valence of ions changes due to dissociation, and the mass-to-charge ratio of product ions often becomes larger than the mass-to-charge ratio of precursor ions. Therefore, even when the mass-to-charge ratio of product ions is larger than the mass-to-charge ratio of precursor ions, it is necessary to detect the product ions with sufficient intensity.

Furthermore, a liquid chromatograph (LC) or gas chromatograph (GC) is connected to the front stage of the Q-TOF mass spectrometer, and a sample containing components (compounds) separated in the time direction by LC or GC is Q-TOF. In the configuration that is introduced into the mass spectrometer, the time during which the same compound is introduced into the Q-TOF mass spectrometer is limited. Therefore, when the CES method is carried out, the number of measurement repetitions is minimized. There is a restriction that a mass spectrum with a wide mass-to-charge ratio range is created. Therefore, it is necessary to appropriately set the mass-to-charge ratio range to be measured in Q-TOFMS for different collision energies.

International Publication No. 2017/017787 (see paragraph [0004]) International Publication No. 2016/042632 Pamphlet International Publication No. 2017/122339 Pamphlet

The present invention has been made to solve the above-mentioned problems, and its main purpose is to create a mass spectrum obtained by integrating product ion spectra obtained under different collision energies at a plurality of stages by the CES method. To provide a Q-TOF mass spectrometer capable of obtaining a mass spectrum in which ions are observed with high sensitivity over a wide range of mass-to-charge ratios.

As described above, generally in OA-TOFMS, the mass-to-charge ratio range of ions that can be observed by one measurement is considerably limited. On the other hand, the present inventors have proposed a novel technique that can increase the overall intensity of ions for ions in a wide mass-to-charge ratio range in OA-TOFMS, as described in Patent Document 3.

In the Q-TOF type mass spectrometer described in Patent Document 3, the inscribed circle radius of each rod electrode constituting a multipole (for example, octupole) type ion guide disposed in the collision cell is from the ion incident side. Also, the rod electrodes are arranged so as to be inclined with respect to the ion optical axis so as to increase on the ion emission side. When a predetermined high-frequency voltage is applied to the plurality of rod electrodes, a gradient of the pseudo-potential depth is formed in the direction of ion travel (the direction of travel from the ion entrance side to the ion exit side), thereby causing the ions in the ion guide. Is accelerated towards its exit. By applying a predetermined DC voltage to the lens electrode disposed at the exit of the collision cell, a potential barrier is formed at the position of the lens electrode and ions are accumulated in the internal space of the ion guide, and then the potential barrier is lowered to Is discharged from the collision cell, and when a predetermined delay time elapses, a voltage is applied in a pulse manner to the orthogonal acceleration unit. Thereby, various ions discharged from the collision cell are accelerated in the direction orthogonal to the traveling direction and introduced into the flight space.

Due to the gradient of the depth of the pseudopotential that forms in the interior space of the ion guide, during mass accumulation, ions with a low mass-to-charge ratio are distributed widely from the entrance to the exit of the ion guide, whereas a high mass-to-charge ratio. Ions tend to concentrate near the exit of the ion guide. Due to such characteristic ion distribution, the longer the delay time, the higher the degree of increase of ions with a large mass-to-charge ratio (= [signal intensity during ion accumulation] / [signal intensity without ion accumulation]) The decrease in the degree of increase of ions having a small mass-to-charge ratio is not so large, and ions having a wide mass-to-charge ratio range can be generally observed with high sensitivity. That is, according to the Q-TOF mass spectrometer described in Patent Document 3, it is possible to observe ions in a wide mass-to-charge ratio range by appropriately determining the delay time. The present inventor pays attention to such an effect, and conceives that the delay time is maintained at a constant value corresponding to the target mass range in a plurality of measurements for different collision energies in the CES method, thereby completing the present invention. It came to.

That is, the present invention made in order to solve the above problems includes a collision cell for bringing an incident ion having a predetermined collision energy into contact with a predetermined gas and dissociating the ion, and ions discharged from the collision cell. An orthogonal acceleration unit that accelerates the ions in a direction orthogonal to the incident axis of the ion flow, and a time-of-flight separation detection unit that separates and detects ions accelerated by the orthogonal acceleration unit according to a mass-to-charge ratio, An orthogonal acceleration time-of-flight mass spectrometer comprising:
a) In order to temporarily hold the ions to be measured, the ions are converged in the vicinity of the ion optical axis by a high-frequency electric field disposed inside the collision cell, and the pseudo potential along the ion optical axis is An ion guide for accelerating ions in the exit direction by a gradient in size or depth, and a part of the collision cell arranged outside the exit end of the ion guide or separate from the collision cell An exit-side gate electrode, and an ion holding portion including:
b) a first voltage generator for applying a DC voltage to the outlet-side gate electrode;
c) a second voltage generator for applying a pulsed voltage for ion ejection to the orthogonal acceleration unit;
d) After applying a predetermined voltage to the outlet side gate electrode to form a potential barrier at the position of the electrode, the first voltage generator is controlled to change the applied voltage so that the potential barrier disappears. Voltage control for controlling the second voltage generation unit so that the ion ejection voltage is applied to the orthogonal acceleration unit when the delay time corresponding to the designated mass range has elapsed from the time when the potential barrier is removed And
e) a measurement control unit that controls the voltage control unit to repeat the measurement while changing the collision energy;
f) a data processing unit that creates a mixed mass spectrum of a designated mass range by accumulating a plurality of mass spectra obtained in respective measurements with respect to different collision energies performed under the control of the measurement control unit;
It is characterized by having.

The present invention is typically a Q-TOF type mass spectrometer in which a quadrupole mass filter is arranged in front of a collision cell. In that case, the collision energy is generally applied to the rod electrode constituting the ion guide included in the ion holding unit disposed in the collision cell and the DC bias voltage applied to the rod electrode constituting the quadrupole mass filter. It depends on the voltage difference from the DC bias voltage.

In the present invention, the measurement control unit controls the voltage control unit to repeat the MS / MS measurement under each collision energy while changing the collision energy. Under the control of the measurement controller, the voltage controller changes the applied voltage so that the potential barrier disappears after applying a predetermined voltage to the outlet gate electrode to form a potential barrier for each measurement. The first voltage generator is controlled so that the voltage for ion ejection is applied to the orthogonal acceleration unit when the delay time corresponding to the designated mass range has elapsed since the potential barrier is removed. 2 The voltage generator is controlled.

The ions introduced into the collision cell with a predetermined collision energy come into contact with a predetermined gas and dissociate to generate product ions. Due to the action of the high-frequency electric field formed by the ion guide, the product ions are converged near the ion optical axis (center axis) in the internal space of the ion guide, and proceed in the exit direction due to the magnitude or depth gradient of the pseudopotential. To do. When a potential barrier is formed in the vicinity of the electrode by the voltage applied to the exit gate electrode, ions that reach the vicinity of the exit gate electrode are pushed back due to the potential barrier. Since the speed at which ions return depends on the mass to charge ratio, the distribution of ions on the ion optical axis differs depending on the mass to charge ratio. When the potential barrier is removed, the ions accumulated in the internal space of the ion guide immediately before that are accelerated by the pseudopotential and sent out to the orthogonal acceleration section through the exit gate electrode.

The smaller the mass-to-charge ratio, the faster the ion travels from the collision cell to the orthogonal acceleration part. However, due to the difference in ion distribution according to the above-mentioned mass-to-charge ratio, if the delay time is appropriately determined, It is possible to perform mass analysis by accelerating ions in a wide range of mass to charge ratios ranging from the ratio to the high mass to charge ratio. Since the mass range of the mass spectrum that the user wants to observe varies depending on the type and purpose of the sample, this mass range is usually designated by the user. In the present invention, the voltage control unit determines a delay time according to the designated mass range, and performs control using the same delay time for measurement under different collision energies.

¡Different collision energies change the type of ion dissociation, so the type of product ions generated also changes. Therefore, although the mass-to-charge ratio range of product ions observed in each measurement varies, as described above, it is possible to measure with high sensitivity for ions with a wide range of mass-to-charge ratios. A mass spectrum with a relatively sufficient peak intensity can be obtained. Since the data processing unit integrates these mass spectra, it is possible to obtain a mixed mass spectrum in which various product ions generated under different collision energies are observed with good balance.

As shown in Patent Document 3, when the relationship between the mass-to-charge ratio of ions with the delay time as a parameter and the degree of increase in ions is examined, when the delay time is below a certain level, the vicinity of a certain mass-to-charge ratio is obtained. The ion increase degree shows a maximum, and the mass-to-charge ratio where the ion increase degree shows a maximum differs depending on the delay time. Therefore, the “delay time according to the designated mass range” is desirably a delay time at which the degree of increase in ions shows a maximum near the mass-to-charge ratio that is the upper limit of the mass range.

For example, when the mass range is m / z 10 to 2000, a delay time that maximizes the degree of ion increase around m / z れ ば 2000 may be selected. As a result, regardless of what mass range is designated, a mixed mass spectrum of good quality can be created so that the peak intensity is generally high for the range of the mass range.

The pseudopotential on the ion optical axis due to the high-frequency electric field in the ion guide is the radius of the circle centered on the central axis where multiple rod-shaped electrodes are in contact, the number of poles of the ion guide (such as the number of rod-shaped electrodes), and the shape of each rod It depends on parameters such as the amplitude and frequency of the high frequency voltage applied to the electrode. Therefore, by changing any of these parameters along the ion optical axis, a pseudo potential magnitude or depth gradient along the ion optical axis can be formed.

For this reason, the present invention can take various modes. As a preferable mode, the ion guide is composed of a plurality of linearly extending rod electrodes surrounding the central axis, and each rod electrode is an entrance of the ion guide. It may be configured to be inclined with respect to the central axis so that the distance from the central axis continuously increases from the side toward the outlet side.

In this configuration, it is possible to form a pseudo-potential with the above-described conditions simply by tilting a rod electrode that is generally arranged parallel to the central axis, so that the configuration is simple and the cost increase is suppressed. It is done. Moreover, it is only necessary to prepare two types of high voltage power supplies having the same amplitude and frequency and opposite phases so that the high frequency voltage applied to each rod electrode simply converges ions. Accordingly, it is possible to avoid the complexity of the power supply system circuit.

According to the present invention, when a mass spectrum obtained by integrating product ion spectra obtained under a plurality of different collision energies by the CES method is created, ions are observed with high sensitivity over a wide range of mass-to-charge ratios. A mass spectrum of good quality can be obtained. Thereby, for example, the accuracy of identification and structural analysis of a compound based on the created mass spectrum can be improved, and it is particularly useful for the analysis of a compound having a complex compound structure.

The block diagram of the principal part of the Q-TOF type | mold mass spectrometer which is one Example of this invention. FIG. 3 is a schematic configuration diagram of an ion optical system and a control system circuit between a quadrupole mass filter and an orthogonal acceleration unit in the Q-TOF type mass spectrometer of the present embodiment. The timing diagram of the voltage applied to the exit lens electrode and the orthogonal acceleration part (extrusion electrode, extraction electrode) in the Q-TOF type mass spectrometer of this example. The figure which shows the relationship between the mass charge ratio of ion and ion multiplication factor which made the delay time based on a measurement result a parameter. Explanatory drawing of the integration process of the mass spectrum in the Q-TOF type | mold mass spectrometer of a present Example.

Hereinafter, a Q-TOF mass spectrometer which is an embodiment of the present invention will be described with reference to the accompanying drawings.

FIG. 1 is a configuration diagram of a main part of the Q-TOF mass spectrometer of the present embodiment. The Q-TOF mass spectrometer of the present embodiment has a multi-stage differential exhaust system configuration, and in the chamber 1, an ionization chamber 2, a first intermediate vacuum chamber 3, a first atmospheric vacuum chamber, 2 An intermediate vacuum chamber 4, a first analysis chamber 5, and a second analysis chamber 6 having the highest degree of vacuum are disposed.

The ionization chamber 2 is provided with an ESI spray 7 for performing electrospray ionization (ESI). When a liquid sample containing the target compound is supplied to the ESI spray 7, charged droplets are sprayed from the tip of the spray 7. In the process where the droplet breaks and the solvent evaporates, ions derived from the target compound are generated. The ionization method is not limited to this. For example, when the sample is a liquid, atmospheric pressure chemical ionization (APCI) method, atmospheric pressure photoionization (APPI) method, probe electrospray ionization (other than ESI) ( An atmospheric pressure ionization method such as PESI method can be used, and a MALDI method can be used when the sample is in a solid state, and an electron ionization (EI) method when the sample is in a gaseous state, A chemical ionization (CI) method or the like can be used.

Various ions generated in the ionization chamber 2 are sent to the first intermediate vacuum chamber 3 through the heating capillary 8, converged by the array type ion guide 9, and sent to the second intermediate vacuum chamber 4 through the skimmer 10. Further, the ions are converged by the multipole ion guide 11 and sent to the first analysis chamber 5. In the first analysis chamber 5, a quadrupole mass filter 12 and a collision cell 13 in which a multipole ion guide 14 functioning as a linear ion trap is provided. Various ions derived from the sample are introduced into the quadrupole mass filter 12, and at the time of MS / MS analysis, a specific mass-to-charge ratio (or mass-to-charge ratio range) corresponding to the voltage applied to the quadrupole mass filter 12 is obtained. The ions that pass through the quadrupole mass filter 12. These ions are introduced into the collision cell 13 as precursor ions, and the precursor ions are dissociated by contact with the collision gas supplied from the outside into the collision cell 13 to generate various product ions.

The ion guide 14 functions as a linear ion trap, and product ions generated by dissociation are temporarily accumulated in the internal space of the ion guide 14. The temporarily accumulated ions are discharged from the collision cell 13 at a predetermined timing, and introduced into the second analysis chamber 6 through the ion passage port 15 while being guided by the ion transport optical system 16. The ion transport optical system 17 is disposed across the first analysis chamber 5 and the second analysis chamber 6 with the ion passage port 15 interposed therebetween.

In the second analysis chamber 6, an orthogonal acceleration unit 17 that is an ion emission source, a flight space 18 in which a reflector 19 is disposed, and an ion detector 20 are provided, and are orthogonal along the ion optical axis C. The ions introduced into the acceleration unit 17 in the X-axis direction are accelerated in the Z-axis direction at a predetermined timing to start flying. In the flight space 18, the ions first freely fly in the space where there is no electric field, and then are turned back by the reflected electric field formed by the reflector 19, and then freely fly in the space without the electric field and reach the ion detector 20 again. . The ion detector 20 outputs a detection signal corresponding to the number or amount of reached ions to the data processing unit 30.

The data processing unit 30 includes a data collection unit 31 and a mass spectrum integration processing unit 32 as functional blocks. The flight time from when the ions leave the orthogonal acceleration unit 17 until they reach the ion detector 20 depends on the mass-to-charge ratio of the ions. Therefore, in the data processing unit 30, the data collection unit 31 collects data obtained by digitizing the detection signals obtained with the passage of time by the ion detector 20, and the mass spectrum integration processing unit 32 performs flight based on the collected data. A time-of-flight spectrum showing the relationship between time and ion intensity is created, and a mass spectrum is created by converting the time of flight into a mass-to-charge ratio based on known calibration information. Mass Spectrum Integration Processing Unit 32 Further, as will be described later, a mass spectrum obtained by integrating a plurality of mass spectra obtained under different collision energies is created.

FIG. 2 is a configuration diagram of an ion optical system from the quadrupole mass filter 12 to the orthogonal acceleration unit 17 in FIG. 1 and a control system circuit related thereto.

The quadrupole mass filter 12 includes four rod electrodes arranged in parallel to the ion optical axis C. However, here, only two rod electrodes located on the XZ plane including the ion optical axis C are depicted (the same applies to the ion guide 14 below). The ion guide 14 is composed of eight rod electrodes, but these eight rod electrodes are not parallel to the ion optical axis C but are distanced from the ion optical axis C in the ion traveling direction (right direction in FIG. 2). Is arranged so that it gradually increases. The rear end surface of the collision cell 13 serves as an exit lens electrode 132, and the exit lens electrode 132 and the ion guide 14 substantially function as a linear ion trap. The ion transport optical system 16 has a configuration in which a plurality (four in this example) of disk-shaped electrode plates having a circular opening at the center are arranged along the ion optical axis C. The orthogonal acceleration unit 17 includes an extrusion electrode 171 and a grid-shaped extraction electrode 172.

Under the control of the control unit 50, the mass filter voltage generation unit 41 applies a predetermined voltage to each rod electrode of the quadrupole mass filter 12. When an ion having a specific mass-to-charge ratio is selected by the quadrupole mass filter 12, this voltage is a voltage obtained by superimposing a high-frequency voltage on a DC voltage, and the DC voltage and the amplitude of the high-frequency voltage are the mass charges to be selected. Depending on the ratio. Further, a DC bias voltage is further added to a voltage obtained by synthesizing the DC voltage and the high frequency voltage. The ion guide voltage generator 42 applies a predetermined voltage to each rod electrode of the ion guide 14. This voltage is obtained by adding a DC bias voltage to a high-frequency voltage for ion focusing. The exit lens electrode voltage generator 43 applies a predetermined DC voltage to the exit lens electrode 132. The ion transport optical system voltage generator 44 applies a predetermined DC voltage to each electrode plate included in the ion transport optical system 16. The orthogonal acceleration part voltage generation part 45 applies a predetermined voltage to the extrusion electrode 171 and the extraction electrode 172, respectively.

The control unit 50 includes, as functional blocks, a CES analysis control unit 51 that performs control during analysis by the CES method, which will be described later, a mass range-delay time correspondence table 52, and a voltage control unit 53 that controls the voltage generation units 41 to 45. . The control unit 50 is connected to an input unit 54 for a user to input various parameters and give instructions.
Part or all of the functions of the control unit 50 and the data processing unit 30 are realized by executing dedicated processing / control software installed in a personal computer, which is a hardware resource, on the computer. can do.

Next, characteristic analysis operations in the Q-TOF type mass spectrometer of the present embodiment will be described with reference to FIGS. 3 to 5 in addition to FIGS. FIG. 3 is a diagram showing the timing of the voltage applied to the exit lens electrode 132, the extrusion electrode 171, and the extraction electrode 172. This analysis operation is performed by performing a plurality of MS / MS analyzes while changing the collision energy as described above, acquiring a mass spectrum (product ion spectrum), and integrating the plurality of mass spectra. This is an operation for creating a mixed mass spectrum of a predetermined mass range.

The user specifies the mass range of the mass spectrum to be observed from the input unit 54 and instructs the execution of the analysis. The CES analysis control unit 51 acquires information on the delay time associated with the designated mass range from the mass range-delay time correspondence table 52. This will be described in detail later. The CES analysis control unit 51 changes the collision energy by a predetermined energy step width over a predetermined collision energy range so that the MS / MS analysis is performed once (or a plurality of times) under different collision energies. The voltage generators 41 to 45 are controlled via the voltage controller 53. The collision energy applied to the ions introduced into the collision cell 13 includes a DC bias voltage applied to the rod electrode of the quadrupole mass filter 12 and a DC bias voltage applied to the rod electrode of the ion guide 14. And the voltage difference. Therefore, the CES analysis control unit 51 adjusts the collision energy by adjusting this voltage difference.

One MS / MS analysis under one collision energy is performed as follows.
As shown in FIG. 2, among various ions derived from the sample components introduced into the quadrupole mass filter 12 from the left, a specific one corresponding to the voltage applied to the rod electrode from the mass filter voltage generation unit 41 Ions having a mass to charge ratio are selected and introduced into the collision cell 13 as precursor ions. At this time, a predetermined collision energy is given to the precursor ions due to the voltage difference, and the precursor ions entering the collision cell 13 come into contact with the collision gas and dissociate to generate various product ions.

At this time, the electric field and ions that cause the ions to converge in the vicinity of the ion optical axis C in the space surrounded by the rod electrodes by the voltage applied from the ion guide voltage generator 42 to the eight rod electrodes constituting the ion guide 14. And a gradient of the pseudopotential depth or magnitude that accelerates the ion guide 14 in the direction from the entrance to the exit. On the other hand, as shown in FIG. 3A, the exit lens electrode voltage generation unit 43 is a positive electrode having the same polarity as the ions during a period in which ions are accumulated in the collision cell 13 during one measurement cycle. A predetermined DC voltage is applied to the exit lens electrode 132. As a result, a potential barrier against ions is formed at the position of the exit lens electrode 132, and discharge of product ions through the exit lens electrode 132 is blocked and accumulated in the internal space of the ion guide 14. When the voltage applied to the exit lens electrode 132 is switched to the negative polarity at time t1 shown in FIG. 3A, the potential barrier disappears, and the accumulated ions are discharged from the collision cell 13 and introduced into the orthogonal acceleration unit 17. Is done.

After a predetermined delay time Td has elapsed from the start of ion ejection, the orthogonal acceleration unit voltage generator 45 applies a positive high voltage pulse (Push) to the push-out electrode 171 as shown in FIG. A negative high voltage pulse (Pull) is applied to 172. As a result, the ions that have passed between the extrusion electrode 171 and the extraction electrode 172 at that time are accelerated in the Z-axis direction, ejected toward the flight space 18, and fly through the flight space 18 to obtain mass charges. The ions are separated according to the ratio and reach the ion detector 20. The ion guide 14 starts accumulating product ions generated by dissociation immediately after discharging the accumulated product ions as described above. In this way, a plurality of MS / MS analyzes are repeatedly performed. Thus, every time MS / MS analysis is executed, data for forming one mass spectrum is stored in the data collection unit 31.

Each time MS / MS analysis is performed, the collision energy is changed stepwise, for example, CE = 10 eV → 15 eV → 20 eV →. At this time, the CES analysis control unit 51 determines the delay time Td from the mass range with reference to the mass range-delay time correspondence table 52 regardless of the collision energy. The relationship between the mass range stored in the mass range-delay time correspondence table 52 and the delay time Td is determined as follows based on the technique described in Patent Document 3.

The eight rod electrodes constituting the ion guide 14 are made into a set of four every other one in the circumferential direction around the ion optical axis C, and the four rod electrodes belonging to one of the two sets have a DC bias. A voltage obtained by adding a positive high-frequency voltage to the voltage is applied, and a voltage obtained by adding a high-frequency voltage having an opposite phase to the same bias DC voltage is applied to the four rod electrodes belonging to the other. A high-frequency electric field having an action of confining ions is formed in a space surrounded by the eight rod electrodes by the high-frequency voltage, but each rod electrode is disposed inclined with respect to the ion optical axis C as described above. Therefore, a gradient of the depth of the pseudo potential is formed in the direction from the entrance to the exit of the ion guide 14.

As disclosed in Patent Document 3 and the like, the pseudo-potential Vp (R) at a position (a radial distance from the center axis C) R formed in a substantially cylindrical space surrounded by the ion guide 14 is Is expressed by the following equation (1).
Vp (R) = {qn ² / (4 mΩ ² )} · (V / r) ² · (R / r) ^{2 (n−1)} (1)
Here, r is the radius of a circle in contact with the ion guide 14, Ω is the frequency of the high frequency voltage, V is the amplitude of the high frequency voltage, n is the number of poles of the ion guide 14, m is the mass of the ion, and q is the charge. That is, by changing any one of the radius r of the circle in contact with the ion guide 14, the frequency Ω or amplitude V of the high frequency voltage, and the number n of poles of the ion guide 14 along the ion optical axis (center axis) C, the pseudo potential Vp (R) can be varied along the ion optical axis C. When a gradient (gradient) exists in the magnitude or depth of the pseudopotential, charged ions are accelerated or decelerated according to the gradient. Various product ions generated in the collision cell 13 are accelerated by the pseudo-potential toward the exit lens electrode 132, but when a potential barrier exists due to the voltage applied to the exit lens electrode 132, the ions are Pushed back by the potential barrier. The traveling speed of the pushed-back ions increases as the mass-to-charge ratio of the ions decreases. For this reason, when a certain time elapses after a certain group of ions reaches the vicinity of the exit lens electrode 132, ions having a smaller mass-to-charge ratio return to a position closer to the entrance. As a result, in the internal space of the ion guide 14, ions having a high mass-to-charge ratio are mainly distributed in the vicinity of the outlet thereof, and ions having a low mass-to-charge ratio are generally distributed widely from the inlet to the outlet. .

As shown in Patent Document 3, the relationship between the delay time Td and the degree of ion increase indicating the ion accumulation effect is characteristic due to the difference in the distribution state of ions due to the mass-to-charge ratio during the above-described ion accumulation. It will be something. FIG. 4 is a graph of experimental results showing the relationship between the mass-to-charge ratio and the degree of ion increase using the delay time shown in Patent Document 3 as a parameter. As described above, since the degree of ion increase is [signal intensity during ion accumulation] / [signal intensity without ion accumulation], if the degree of ion increase is 1, it can be said that there is no effect of ion accumulation. As shown in this figure, when the delay time Td is about 100 us or less, the ion amplification peak moves in the direction in which the mass-to-charge ratio increases as the delay time Td becomes longer. The degree of increase in ions in the region has not decreased so much. That is, by increasing the delay time T, ions in a wide mass-to-charge ratio range can be observed. This is an effect of the characteristic ion accumulation operation in the ion guide 14 as described above.

In the conventional general linear ion trap, the width of the mass-to-charge ratio range in which the ion accumulation effect can be obtained is limited, and ions in a wide mass-to-charge ratio range cannot be accumulated. In contrast, the ion guide 14 used in the Q-TOF type mass spectrometer of this embodiment can accumulate ions in a wide range of mass-to-charge ratios with a relatively high degree of ion increase. Therefore, based on the relationship shown in FIG. 4, for the mass range to be observed, the delay time Td is selected such that the peak of ion enhancement exists near the upper limit (maximum mass-to-charge ratio) of the mass range. For example, when the mass range is m / z 10 to 2000, 80 us where the peak of ion enhancement exists in the vicinity of m / z 2100 is selected as the delay time Td. In addition, when the mass range is m / z１０００10 to 1000, 50 us showing the peak of the degree of increase in ions near m / z 1000 is selected as the delay time Td, and when the mass range is m / z 10 to 3000. Selects 100 us as the delay time Td at which the degree of increase in ions reaches a peak in the vicinity of m / z 3000. In this way, an appropriate delay time Td is determined for each of the mass ranges that can be set by the input unit 54.

When the delay time Td is set as described above, it is ensured that the ion increase degree is relatively high (greater than at least 1) over the entire mass-to-charge ratio range of the mass range corresponding to the delay time Td. . Specifically, for example, if the delay time Td is set to 40 us when the mass range is m / z 10 to 1000, a high degree of ion enhancement is obtained in the low mass to charge ratio region, but about m / z 700. In the above range, the degree of increase in ions decreases rapidly. On the other hand, if the delay time Td is 50 us when the mass range is m / z 10 to 1000, it is guaranteed that the ion increase degree is 4 or more over almost the entire mass-to-charge ratio range of the mass range. In addition, the degree of ion increase is always greater than when the delay time Td is greater than 50 us. Thereby, it is possible to detect with high sensitivity to ions appearing in any region of the mass range range designated by the user, and a good mass spectrum can be created.

FIG. 5 is an explanatory diagram of mass spectrum integration processing in the CES method. In this example, as described above, MS / MS analysis is performed while changing the collision energy every 5 eV in the range of CE = 10 to 40 eV, and mass spectra are acquired, and these mass spectra are integrated to obtain a final mass spectrum. (CES mass spectrum) is created. As described above, although the collision energy is different, the delay time Td determined corresponding to the mass range is constant. Even if the precursor ions are the same, the types of product ions generated are different because of different collision energies, but the product ions appearing at any position within the mass-to-charge ratio range of the mass range are detected with high sensitivity. As a result, peaks derived from product ions generated under each collision energy are observed in the CES mass spectrum in a well-balanced manner, and the identification and structural analysis of compounds based on the mass spectrum can be performed smoothly.

It should be noted that the relationship between the degree of ion increase and the delay time shown in FIG. 4 is merely an actual measurement example, and varies depending on the structure of the apparatus and analysis conditions. Therefore, by performing experiments or simulations assuming analysis conditions for each model by the device manufacturer, the relationship between the degree of ion increase and the delay time is examined, and a mass range-delay time correspondence table is created based on the results. It is preferable to keep it.

In the above-described embodiment, the rod electrode constituting the ion guide 14 is disposed so as to be inclined with respect to the ion optical axis C. However, as described above, the pseudo potential along the ion optical axis C in the collision cell 13 is reduced. The gradient is also formed by changing the radius of a circle in contact with the ion guide 14, the frequency or amplitude of the high-frequency voltage applied to each rod electrode, the number of poles of the ion guide 14 and the like along the ion optical axis C. . From this point of view, as described in Patent Document 3, the ion guide 14 can be variously deformed. Specifically, the rod electrode may not have a linear shape but may have a bent shape in the middle or may have a curved shape in the middle. Also, each rod electrode is not a single electrode, but is divided into a plurality of divided rod electrodes divided in the extending direction, and the distance from the ion optical axis of each divided rod electrode is gradually increased from the entrance side to the exit side. You may arrange | position so that it may become large. Furthermore, the substantial number of poles may be changed by changing the cross-sectional shape of the split rod electrode.

Further, the above-described embodiment is merely an example of the present invention, and it is obvious that any change, modification, addition or the like as appropriate within the scope of the present invention is included in the scope of the claims of the present application.

DESCRIPTION OF SYMBOLS 1 ... Chamber 2 ... Ionization chamber 3 ... 1st intermediate | middle vacuum chamber 4 ... 2nd intermediate | middle vacuum chamber 5 ... 1st analysis chamber 6 ... 2nd analysis chamber 7 ... ESI spray 8 ... Heating capillary 9 ... Array type ion guide 10 ... Skimmer DESCRIPTION OF SYMBOLS 11 ... Multipole type ion guide 12 ... Quadrupole mass filter 13 ... Collision cell 132 ... Exit lens electrode 14 ... Ion guide 15 ... Ion passage port 16 ... Ion transport optical system 17 ... Orthogonal acceleration part 171 ... Extrusion electrode 172 ... Extraction Electrode 18 ... Flight space 19 ... Reflector 20 ... Ion detector 30 ... Data processing unit 31 ... Data collection unit 32 ... Mass spectrum integration processing unit 41 ... Mass filter voltage generation unit 42 ... Ion guide voltage generation unit 43 ... Exit side gate electrode Voltage generation unit 44 ... Ion transport optical system voltage generation unit 45 ... Orthogonal acceleration unit voltage generation unit 50 ... Control unit 51 ... CES analysis control unit 52 ... Delay During correspondence table 53 ... voltage control unit 54 ... input portion C ... ion optical axis

Claims (3)

A collision cell for bringing ions incident with a predetermined collision energy into contact with a predetermined gas for dissociation, and an orthogonal for accelerating ions ejected from the collision cell in a direction orthogonal to the incident axis of the ion flow An orthogonal acceleration time-of-flight mass spectrometer comprising: an acceleration unit; and a time-of-flight separation detection unit that separates and detects ions accelerated by the orthogonal acceleration unit according to a mass-to-charge ratio,
a) In order to temporarily hold the ions to be measured, the ions are converged in the vicinity of the ion optical axis by a high-frequency electric field disposed inside the collision cell, and the pseudo potential along the ion optical axis is An ion guide for accelerating ions in the exit direction by a gradient in size or depth, and a part of the collision cell arranged outside the exit end of the ion guide or separate from the collision cell An exit-side gate electrode, and an ion holding portion including:
b) a first voltage generator for applying a DC voltage to the outlet-side gate electrode;
c) a second voltage generator for applying a pulsed voltage for ion ejection to the orthogonal acceleration unit;
d) After applying a predetermined voltage to the outlet side gate electrode to form a potential barrier at the position of the electrode, the first voltage generator is controlled to change the applied voltage so that the potential barrier disappears. Voltage control for controlling the second voltage generation unit so that the ion ejection voltage is applied to the orthogonal acceleration unit when the delay time corresponding to the designated mass range has elapsed from the time when the potential barrier is removed And
e) a measurement control unit that controls the voltage control unit to repeat the measurement while changing the collision energy;
f) a data processing unit that creates a mixed mass spectrum of a designated mass range by accumulating a plurality of mass spectra obtained in respective measurements with respect to different collision energies performed under the control of the measurement control unit;
An orthogonal acceleration time-of-flight mass spectrometer. The orthogonal acceleration time-of-flight mass spectrometer according to claim 1,
The delay time corresponding to the designated mass range is a delay time that maximizes the effect of accumulating ions in the internal space of the ion guide near the mass-to-charge ratio that is the upper limit of the mass range. Orthogonal acceleration time-of-flight mass spectrometer. The orthogonal acceleration time-of-flight mass spectrometer according to claim 1,
The ion guide is composed of a plurality of linearly extending rod electrodes surrounding the central axis, and each rod electrode is continuously increased in distance from the central axis from the inlet side to the outlet side of the ion guide. The orthogonal acceleration time-of-flight mass spectrometer is provided so as to be inclined with respect to the central axis.

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