JP7673609B2 - Mass Spectrometer - Google Patents

Description

The present invention relates to a mass spectrometer.

Mass spectrometers are widely used to identify and quantify components contained in samples. In mass spectrometers, ions generated from sample components are mass-separated and the ion intensity for each mass-to-charge ratio is measured. A mass spectrum is then created with two axes of mass-to-charge ratio and ion intensity, and the component is identified based on the degree of match with mass spectra of known substances. The component is also quantified based on the intensity of the mass peaks in the mass spectrum.

When the sample component is a relatively large molecule, it is difficult to identify the component from the ions generated from the sample component. Therefore, MS/MS analysis is performed in which ions with a specific mass-to-charge ratio are selected as precursor ions from the ions generated from the sample component, and the precursor ions are fragmented to generate product ions, which are mass-separated to measure the intensity of the ions for each mass-to-charge ratio. In MS/MS analysis, the partial structure of the sample component is inferred from the mass-to-charge ratios of various product ions, and the sample component is identified.

Because mass spectrometry separates ions according to their mass-to-charge ratio, it is not possible to separate ions with the same mass-to-charge ratio. For example, butane and isobutane are structural isomers with different bonding positions of the methyl groups, but because they have the same mass, these ions cannot be separated. Furthermore, in the case of structural isomers, even if precursor ions are cleaved to generate product ions, only the same type of product ion is often generated, making it difficult to distinguish between the two.

Therefore, in the past, other measurement methods have been used to obtain information on the geometric structure of molecules (interatomic distances and bond angles) that cannot be obtained by mass spectrometry. Examples of such measurement methods include rotational spectrometry, electron beam diffraction measurement, and X-ray diffraction measurement. In rotational spectrometry, microwaves are irradiated onto a sample gas to measure the absorbance (absorption measurement), or light emitted from the sample gas is spectroscopically measured, but the sensitivity is lower than that of diffraction methods such as electron beam diffraction measurement and X-ray diffraction measurement. In addition, the elastic scattering cross section of X-ray diffraction measurement is 10 ^-5 to 10 ^-4 times smaller than that of electron beam diffraction (for example, Non-Patent Document 1), and the sensitivity of measurements of sample gas is lower than that of electron beam diffraction. For these reasons, it has been proposed to obtain the geometric structure of molecules by electron beam diffraction measurement as described in Non-Patent Documents 2-5.

Non-Patent Documents 2 and 3 describe electron beam diffraction devices. In these devices, neutral gas molecules are introduced into an ion trap and ionized (photoionized) by irradiating them with laser light, and the multiple types of ions generated are then trapped in the ion trap, after which mass selection is performed in the ion trap to trap only the ions to be analyzed. An electron beam is then irradiated onto the ions trapped in the ion trap to obtain an electron beam diffraction image. Information on the geometric structure of the molecule is obtained by analyzing this electron beam diffraction image.

Non-Patent Document 4 describes an apparatus that combines an apparatus for performing electron beam diffraction measurements with a mass analyzer. This apparatus is equipped with a deflection section downstream of the ionization section that deflects the flight direction of ions, and the deflection direction is switched by the deflection section to introduce ions generated in the ionization section into either an ion trap or a time-of-flight mass separator. In the ion trap, a diffraction image is obtained by irradiating an electron beam, as in the apparatuses of Non-Patent Documents 2 and 3, and information on the molecular structure of the ions is obtained. Meanwhile, the time-of-flight mass separator obtains a mass spectrum to monitor the state of ion generation in the ion source.

M. Haneda, "Observation of ultrafast structural dynamics using tabletop femtosecond electron diffraction," Journal of the Vacuum Society of Japan, Vol. 59 (2016), No. 2 Keiko Kato, Dissertation Abstract "Development of an Ion Trap Electron Diffraction Apparatus and Its Application to Determining the Structure of Molecular Ions and Tracking Their Reactions", 2006, Graduate School of Science, The University of Tokyo, [online], [Retrieved December 21, 2020], Internet <URL:http://gakui.dl.itc.u-tokyo.ac.jp/cgi-bin/gazo.cgi?no=121041> Hidetaka Tanaka and 3 others, Abstract of the 9th Molecular Science Symposium 2015 Tokyo Lecture "Ion trap electron diffraction apparatus for determining the geometric structure of molecular ions", [online], August 31, 2015, Molecular Science Society, [Retrieved December 21, 2020], Internet <URL: http://molsci.center.ims.ac.jp/area/2015/PDF/pdf/1P012_w.pdf> D. Schooss, M.N. Blom, J.H. Parks, B.V. Issendorff, H. Haberland, and M.M. Kappes, "The structure of Ag55+ and Ag55-: Trapped ions electron diffraction and density functional theory", Nano Lett. 5 (2005) 1972. M. Marier-Brost, D. B. Cameron, M. Rokni, and J.H. Parks, "Electron diffraction of trapped cluster ions", Phys. Rev. A 59 (1999) R3162.

By combining a configuration for performing electron diffraction measurements, such as those described in Non-Patent Documents 2-5, with a mass spectrometer, it becomes possible to obtain information on the geometric structure of molecules (interatomic distances and bond angles) with higher sensitivity than rotational spectrum measurements or X-ray diffraction measurements when identifying structural isomers that are difficult to distinguish by mass spectrometry, and identify sample components with a single device based on mass spectrometry. However, with conventionally proposed electron diffraction devices, the electron beam must be continuously irradiated for a long period of time, such as 5 to 6 hours, to obtain a diffraction image with sufficient intensity for analysis. On the other hand, mass analysis can be performed in a short period of time, such as a few minutes. Thus, with conventional configurations, the time required for auxiliary electron diffraction measurements is significantly longer than the time required for mass analysis, which is the main measurement. Therefore, there is a demand for a technology that can perform electron diffraction measurements more efficiently.

Here, we have taken the example of performing measurements to obtain information on the geometric structure of molecules in addition to mass spectrometry, but similar problems to those described above arise when performing various secondary measurements in addition to mass spectrometry to obtain information that cannot be obtained by mass spectrometry.

The problem that this invention aims to solve is to provide an apparatus that can perform both mass spectrometry and secondary measurements to obtain information that cannot be obtained by mass spectrometry in a single measurement. It is also to provide technology that can perform secondary measurements in such an apparatus more efficiently than ever before.

In order to solve the above problems, the mass spectrometer according to the present invention is
an ionization unit for generating ions from a sample;
a mass separation unit that separates the ions generated in the ionization unit according to their mass-to-charge ratio ;
an ion detector that detects ions separated by the mass separation unit;
an ion trapping unit that traps the ions separated by the mass separation unit;
and a sub-measurement unit that measures a physical quantity of the ions trapped in the ion trapping unit other than the mass-to-charge ratio.

In the mass spectrometer according to the present invention, mass analysis can be performed by mass-separating the ions generated in the ionization section in the mass separation section and detecting them with an ion detector. In addition, the ions generated in the ionization section can be mass-separated in the mass separation section to select the ions to be analyzed, and then captured in the ion trapping section to measure physical quantities other than the mass-to-charge ratio (secondary measurement). The secondary measurement can be, for example, irradiating the ions captured in the ion trapping section with an electromagnetic wave (light beam, etc.) or a particle beam, and detecting the electromagnetic wave (light, etc.) or particles emitted from the ion trapping section. Specifically, for example, after accumulating the ions to be analyzed in the ion trapping section, an electron beam can be irradiated thereon for a predetermined time, and the electron beam diffracted by the ions in the ion trapping section can be detected to perform electron beam diffraction measurement. Although mass analysis alone cannot distinguish isomers with the same mass-to-charge ratio, the mass spectrometer according to the present invention can obtain information on the molecular structure and distinguish isomers by performing, for example, the above-mentioned electron beam diffraction measurement as a secondary measurement. In addition, by appropriately changing the flight path of the ions, the mass spectrometer of the present invention can perform both mass analysis, which separates and detects the ions generated in the ionization section, and secondary measurement, which captures the ions after the mass separation and measures physical quantities other than the mass-to-charge ratio of the ions, in a single measurement.

If mass separation is performed in an ion trapping section (typically a three-dimensional ion trap) with an excessive amount of ions trapped in the ion trapping section, the electric field in the ion trapping section is distorted by the electric charge (space charge) of the ions themselves, making it impossible to perform mass separation normally. Therefore, in a conventional configuration in which mass separation is performed in an ion trapping section, there is a limit to the amount of ions that can be trapped in the ion trapping section. Even if the maximum amount of ions generated from a sample is captured using a conventional device, the amount of ions decreases due to the subsequent mass separation. In contrast, the mass spectrometer of the present invention selects ions to be analyzed using the mass separation section and introduces only the target ions to be analyzed into the ion trapping section, so that the maximum amount of target ions can be captured and used for secondary measurement, and high-intensity measurement data can be obtained more efficiently and in a shorter time than in the past.

The ion trapping section may be disposed between the mass separation section and the ion detector, for example, or a deflection section for deflecting the flight direction of the ions may be provided between the mass separation section and the ion detector, and the ion trapping section may be disposed on the flight path of the ions deflected by the deflection section. In the former case, the ion trapping section may not be operated, and the ions mass-separated in the mass separation section may be allowed to pass through as is and detected by the ion detector for mass analysis, and the ions mass-separated in the mass separation section may be captured in the ion trapping section for secondary measurement. In the latter case, the flight path of the ions during mass analysis and the flight path of the ions during secondary measurement are different, so both measurements can be performed in parallel.

1 is a schematic diagram of an embodiment of a mass spectrometer according to the present invention; 4 shows measurement conditions for target compounds in a measurement example using the mass spectrometer of this embodiment. FIG. 4 is a diagram for explaining the measurement content executed in the present embodiment. FIG. 4 is a diagram for explaining a rectangular voltage applied to an ion trap in this embodiment. 2 shows an ion trap used in the mass spectrometer of this embodiment. Simulation results for the spread of ions in the X-axis direction inside the ion trap when the phase of the rectangular voltage applied to the ion trap is 0°. Simulation results for the spread of ions in the X-axis direction inside the ion trap when the phase of the rectangular voltage applied to the ion trap is 90°. Simulation results for the spread of ions in the X-axis direction inside the ion trap when the phase of the rectangular voltage applied to the ion trap is 180°. Simulation results for the spread of ions in the X-axis direction inside the ion trap when the phase of the rectangular voltage applied to the ion trap is 270°. Simulation results for the spread of ions in the Z-axis direction inside the ion trap when the phase of the rectangular voltage applied to the ion trap is 0°. Simulation results for the spread of ions in the Z-axis direction inside the ion trap when the phase of the rectangular voltage applied to the ion trap is 90°. Simulation results for the spread of ions in the Z-axis direction inside the ion trap when the phase of the rectangular voltage applied to the ion trap is 180°. Simulation results for the spread of ions in the Z-axis direction inside the ion trap when the phase of the rectangular voltage applied to the ion trap is 270°. FIG. 2 is a diagram for explaining electron beam diffraction measurement. 1 is a chromatographic mass spectrometer using the mass spectrometer of this embodiment. An ion mobility spectrometry-mass spectrometry apparatus using the mass spectrometry apparatus of this embodiment. A chromatograph-ion mobility spectrometer-mass spectrometer using the mass spectrometer of this embodiment. 13 shows an example of the arrangement of each part in a mass spectrometer according to a modified example. 4 shows examples of sub-measurements that can be performed in a mass spectrometer according to the present invention. 1 shows an example of the schematic configuration of a mass spectrometer that performs various secondary measurements. 3 shows another schematic configuration example of a mass spectrometer for performing various secondary measurements.

An embodiment of a mass spectrometer according to the present invention will be described below with reference to the drawings.

Figure 1 is a schematic diagram of the mass spectrometer 1 of this embodiment. The mass spectrometer 1 of this embodiment is composed of an apparatus main body 10 and a control and processing unit 4. The apparatus main body 10 is provided with an ionization chamber 20, a first intermediate vacuum chamber 21, a second intermediate vacuum chamber 22, and an analysis chamber 23. In addition, an electron beam irradiation unit 30 is connected to the analysis chamber 23. An appropriate voltage is applied from a voltage application unit 5 to each part in the apparatus main body 10 during measurement based on the control by the control and processing unit 4.

The ionization chamber 20 is at approximately atmospheric pressure, the first intermediate vacuum chamber 21 is a low vacuum chamber evacuated by a rotary pump (not shown), and the second intermediate vacuum chamber 22, the analysis chamber 23, and the inside of the electron beam irradiation unit 30 are high vacuum chambers evacuated by a turbomolecular pump (not shown). The first intermediate vacuum chamber 21, the second intermediate vacuum chamber 22, and the analysis chamber 23 are configured as a multi-stage differential pumping system in which the degree of vacuum increases in this order.

The ionization chamber 20 is equipped with an electrospray ionization probe (ESI probe) 201 that applies an electric charge to the sample solution and sprays it. The ionization chamber 20 and the first intermediate vacuum chamber 21 are connected via a thin-diameter heated capillary 202. In this embodiment, the ESI probe 201 is used as the ionization unit, but an appropriate ionization unit can be used depending on the characteristics of the sample.

In the first intermediate vacuum chamber 21, an ion lens 211 consisting of multiple annular electrodes is placed, which focuses ions while transporting them to the rear stage. The first intermediate vacuum chamber 21 and the second intermediate vacuum chamber 22 are separated by a skimmer 212 with a small hole at the top.

The second intermediate vacuum chamber 22 is provided with a first ion guide 221 and a second ion guide 222, each of which is made up of multiple rod electrodes and focuses ions while transporting them to the subsequent stage. The second intermediate vacuum chamber 22 and the analysis chamber 23 are connected through a small hole formed in the partition wall.

In the analysis chamber 23, a front quadrupole mass filter (Q1) 231, a collision cell 232, a rear quadrupole mass filter (Q3) 235, a deflection section 236, and an ion detector 237 are arranged. The front quadrupole mass filter 231 is composed of a pre-rod electrode 2311, a main rod electrode 2312, and a post rod electrode 2313. A quadrupole rod electrode 234 is arranged inside the collision cell 232. In addition, the collision cell 232 is provided with a gas inlet for introducing a collision induced dissociation gas (CID gas) such as argon gas or nitrogen gas. The rear quadrupole mass filter 235 is composed of a pre-rod electrode 2351, a main rod electrode 2352, and a post rod electrode 2353. Four rod electrodes 2361 are arranged in the deflection section 236. In this embodiment, the deflection unit 236 deflects the flight direction of the ions as described below, but the deflection unit can be any suitable configuration capable of deflecting the flight direction of the ions.

The analysis chamber 23 also includes an ion trap 31 and an electron beam detector 32. The ion trap 31 is composed of a ring electrode 311, an entrance end cap electrode 312, and an exit end cap electrode 313, which are arranged on either side of the ring electrode 311. The entrance end cap electrode 312 has an opening 314 for introducing ions and electron beams. The exit end cap electrode 313 has an opening 315 for discharging ions and electron beams. The ion trap 31 is disposed in a vacuum chamber 316, and in addition to the openings corresponding to the openings 314 and 315, a gas inlet 317 for introducing a cooling gas into the ion trap 31 is provided on the wall of the vacuum chamber 316. The inside of the vacuum chamber 316 is evacuated to a high vacuum by a turbo molecular pump (not shown).

The electron beam detection unit 32 includes a Faraday cup 321, a microchannel plate 322, a fluorescent screen 323, and a CCD camera 324. The microchannel plate 322 is disposed outside the exit endcap electrode 313 in the ion trap 31. The Faraday cup 321 is disposed near the surface of the microchannel plate 322, at a position on the irradiation axis C2 of the electron beam. The fluorescent screen 323 is attached to the rear surface of the microchannel plate 322. The CCD camera 324 is disposed on the rear surface side of the fluorescent screen 323, at a position where the CCD camera 324 can capture an image of the rear surface.

The electron beam irradiation unit 30 is equipped with an electron gun 301 and an electron lens 302. In the electron beam irradiation unit 30, the incident energy of the electron beam irradiated onto the ions when performing electron beam diffraction measurement can be changed.

In addition to the memory unit 41, the control/processing unit 4 includes the following functional blocks: a measurement condition setting unit 43, a measurement control unit 44, an analysis processing unit 45, an electron beam diffraction image estimation unit 46, and a molecular structure estimation unit 47. A compound database 411 is stored in the memory unit 41. The molecular structure estimation unit 47 includes a first molecular structure estimation unit 471, a second molecular structure estimation unit 472, and a third molecular structure estimation unit 473. The actual entity of the control/processing unit 4 is a general personal computer, and the processor of the personal computer functions as each of the above units by executing a mass analysis program 42 pre-installed in the computer. An input unit 6 and a display unit 7 are also connected to the control/processing unit 4.

The compound database 411 contains information such as measurement conditions and analysis results for a large number of known compounds. Measurement conditions include, for example, the time it takes for a compound to flow out of a liquid chromatograph column (retention time) and the mass-to-charge ratio of a precursor ion and product ion pair (MRM transition) that characterizes the compound. Analysis result information includes, for example, MS/MS spectrum data and electron diffraction image data for each compound. The electron diffraction image data may be experimentally obtained by measuring a standard sample, or may be theoretically calculated based on the molecular structure of the compound. For example, first-principles calculations can be used for such theoretical calculations.

Next, the measurement of a sample using the mass spectrometer 1 of this embodiment will be described. Here, an example will be described in which a liquid chromatograph is placed in front of the mass spectrometer 1 (see FIG. 15), a sample is introduced into the liquid chromatograph, and components contained in the sample are separated from each other in the column of the liquid chromatograph and measured by the mass spectrometer 1. However, the provision of a component separation means such as a chromatograph is not essential to the present invention. For example, even when measuring a sample containing multiple compounds, if ions derived from the compound to be measured can be separated from ions derived from other compounds by mass separation alone, the sample may be directly introduced into the mass spectrometer 1 without using a component separation means.

First, the measurement condition setting unit 43 reads out a list of compounds stored in the compound database 411 and displays it on the display unit 7. When the user selects a compound to be measured from the list, the measurement condition setting unit 43 creates a method file that describes the measurement conditions described in the compound database 411. Then, a batch file for executing the measurement is created from these method files. Note that in this embodiment, the process in which the user selects a compound to be measured from the compound database 411 corresponds to inputting information on molecular structure candidates in the present invention, and the measurement condition setting unit 43 in this embodiment functions as a molecular structure candidate input receiving unit in the present invention (see [Aspects] described below).

As a specific example, the case where compounds A to D shown in FIG. 2 are the measurement targets will be described here. Among compounds A to D, compounds C and D are structural isomers. Some structural isomers can be separated from each other using a liquid chromatograph or gas chromatograph column, but here, we consider a case where compounds C and D have the same retention time, precursor ion, and product ion effluent from the liquid chromatograph column (i.e., compounds C and D cannot be distinguished from each other using liquid chromatograph mass spectrometry alone). Therefore, in this example, MRM measurement is performed for all compounds A to D, and electron beam diffraction measurement is also performed for compounds C and D. In other words, as shown in FIG. 3, a batch file is created in which MRM measurement of compound A is performed in time zone 1, MRM measurement of compounds A and B is performed alternately in time zone 2, MRM measurement of compound B is performed in time zone 3, and MRM measurement and electron beam diffraction measurement of compounds C and D are performed in time zone 4. The user may specify whether or not to perform electron beam diffraction measurement, or the measurement condition setting unit 43 may automatically set electron beam diffraction measurement for a pair of compounds having the same retention time, mass-to-charge ratio of precursor ion, and mass-to-charge ratio of product ion. Also, for ease of explanation, only one MRM transition is measured for one compound here, but multiple MRM transitions may be measured.

After creating the batch file, when the user issues a command to perform a measurement by performing a specified input operation, the measurement control unit 44 performs the measurement in the following procedure.

First, a sample is introduced into a liquid chromatograph. The sample components separated in the chromatograph column are sequentially introduced into the ESI probe 201 and ionized.

After measurement starts, when the first time slot (time slot 1) described in the batch file is reached, the compound described in that time slot is measured. In time slot 1, MRM measurement of compound A is performed. After that, in each time slot, MRM measurement and electron beam diffraction measurement are performed based on the contents described in the batch file.

We will briefly explain the MRM measurements performed during time periods 1 to 4. The measurement conditions for the MRM measurements are the same as in the past.

The sample components flowing out of the liquid chromatograph column are ionized by the ESI probe 201, then introduced into the first intermediate vacuum chamber 21 through the heated capillary 202, and then focused onto the ion optical axis C1 by the ion lens 211. The ions focused by the ion lens 211 pass through the skimmer 212 and enter the second intermediate vacuum chamber 22. The ions that enter the second intermediate vacuum chamber 22 are focused onto the ion optical axis C1 by the first ion guide 221 and the second ion guide 222, and enter the analysis chamber 23.

In the analysis chamber 23, first, precursor ions of the compound to be measured are selected by the front-stage quadrupole mass filter 231 and introduced into the collision cell 232. A predetermined amount of a predetermined type of inert gas (typically argon gas) is sealed in the collision cell 232 as a collision gas. A potential difference is provided between the post rod electrode 2313 of the front-stage quadrupole mass filter 231 and the entrance of the collision cell 232, and this potential difference provides energy (collision energy) to the precursor ions of the compound to be measured, causing them to enter the collision cell. In the collision cell 232, product ions are generated from the precursor ions by collision with inert gas molecules.

Then, in the rear quadrupole mass filter 235, only product ions having a predetermined mass-to-charge ratio (described in the method file) are selected. The ions selected by the rear quadrupole mass filter 235 pass directly through the deflection unit 236 and are detected by the ion detector 237. The output signals from the ion detector 237 are sequentially sent to the memory unit 41 and stored.

Next, we will explain the electron diffraction measurement performed during time period 4.

In electron diffraction measurements, as in the MRM measurements described above, ions of a predetermined mass-to-charge ratio are selected as precursor ions in the front-stage quadrupole mass filter 231, and the precursor ions are dissociated in the collision cell 232 to generate product ions. Then, ions of a predetermined mass-to-charge ratio are selected as ions to be analyzed in the rear-stage quadrupole mass filter 235. In electron diffraction measurements, product ions that have the same mass-to-charge ratio but contain parts with different molecular structures are used as the ions of the above-mentioned predetermined mass-to-charge ratio selected by the rear-stage quadrupole mass filter 235 as the ions to be analyzed.

When performing electron beam diffraction measurements, the inside of the vacuum chamber 316 is evacuated to a high vacuum in advance, and neutral gas molecules remaining inside the ion trap 31 are discharged. Then, a voltage of the opposite polarity to that of the product ions is applied to one of the four rod electrodes 2361 of the deflection section 236 (the rod electrode 2361 located at the lower left in Figure 1), and a voltage of the same polarity as that of the product ions is applied to the other rod electrodes 2361. By applying an appropriate voltage to these four rod electrodes 2361, the flight direction of the ions that have passed through the rear-stage quadrupole mass filter 235 is deflected by 90 degrees (downward in Figure 1).

The product ions, whose flight direction has been deflected by the deflection unit 236, are captured in the ion trap 31, cooled by collision with a cooling gas (typically helium gas) that is temporarily introduced into the ion trap 31 through the gas inlet 317, and collected in the center of the ion trap 31. After the product ions are accumulated and cooled for a predetermined time in the ion trap 31, an electron beam is irradiated from the electron beam irradiation unit 30 into the inside of the ion trap 31.

In conventional electron diffraction measurements, ions generated from a sample are directly stored in an ion trap, and then mass separation is performed in the ion trap to select the ions to be measured. When storing ions generated from a sample, if an excessive amount of ions are stored, the electric field inside the ion trap is distorted by the electric charge of the ions themselves (called "space charge"), making it impossible to perform normal mass separation. Therefore, at the stage of storing ions generated from a sample, there is a limit to the amount that can be stored in the ion trap. In addition, conventionally, ions generated from a sample are introduced into an ion trap, and the ions to be measured are mass separated and selected in the ion trap. Therefore, even if the maximum amount of ions that can be stored is stored at the beginning, the amount of ions to be analyzed contained therein is less than that.

In contrast, in the mass spectrometer of this embodiment, the product ions to be analyzed are selected using the front-stage quadrupole mass filter 231, the collision cell 232, and the rear-stage quadrupole mass filter 235, and then introduced into the ion trap 31. Therefore, there is no need to perform mass separation within the ion trap 31, and only the product ions to be analyzed can be introduced into the ion trap 31 without limiting the amount of ions accumulated in the ion trap 31.

Conventionally, the entrance end cap electrode and the exit end cap electrode are held at ground potential, and ions are trapped in the ion trap by applying a high-frequency sine voltage to the ring electrode, and the mass-to-charge ratio (range) of the trapped ions is increased or decreased by increasing or decreasing the amplitude (voltage driving) while keeping the frequency of the sine voltage constant. With conventional methods, the amplitude of the sine voltage must be increased as the mass-to-charge ratio of the ions to be trapped increases, which requires the use of a large, expensive power supply capable of outputting high voltages. In addition, there are problems in that the application of a high voltage makes discharges more likely to occur, and the application of a time-varying high voltage can adversely affect the flight path of the electron beam.

On the other hand, in this embodiment, the entrance end cap electrode 312 and the exit end cap electrode 313 are set to ground potential, and a rectangular voltage generated by the voltage application unit 5 using a digital circuit is applied to the ring electrode 311 of the ion trap 31. An ion trap that captures ions by applying a rectangular voltage in this way is also called a digital ion trap (DIT). In a DIT, the frequency is changed over a wide range (frequency driven) while keeping the amplitude of the rectangular voltage constant to change the mass-to-charge ratio (range) of the ions captured in the ion trap 31. In a digital ion trap, the amplitude of the rectangular voltage is constant regardless of the mass-to-charge ratio of the ions to be captured, so there is no need to use a large and expensive power supply. There is also no need to worry about discharge. Furthermore, since the frequency drive can change the frequency over a wide range, it is possible to cover a wider mass-to-charge ratio range and capture more types of ions than conventional voltage-driven ion traps. For example, by lowering the frequency, it is possible to capture ions with a large mass-to-charge ratio that are difficult to capture with conventional voltage-driven ion traps, or to capture fine charged particles that are much larger than ions. Furthermore, while a low-frequency rectangular voltage is applied to capture precursor ions with a large mass-to-charge ratio, the captured precursor ions can be fragmented (i.e., dissociated) using laser light or the like, and the frequency of the rectangular voltage can be instantly switched to a higher frequency (frequency jump) so that the fragment ions with a small mass-to-charge ratio generated by the fragmentation of the precursor ions are captured in the ion trap. In addition, by injecting the electron beam at a timing when the rectangular voltage (high-frequency voltage) reaches a specified phase, as described below, the possibility of adversely affecting the flight path of the electron beam can be eliminated.

In the mass spectrometer 1 of this embodiment, this rectangular voltage is applied to the ring electrode 311 for a predetermined time to trap product ions in the ion trap 31. At this time, the spatial distribution of ions inside the ion trap 31 changes with the change in phase of the rectangular voltage applied to the ring electrode 311. In the following description, the phase at the point when the applied voltage changes from negative to positive is set to 0°, and the phase at the point when it changes from positive to negative is set to 180°, as shown in Fig. 4. Also, as shown in Fig. 5, the axis of symmetry of the ion trap 31 (the axis passing through the opening 314 of the entrance endcap electrode 312 and the opening 315 of the exit endcap electrode 313) is set to the Z axis, and one direction perpendicular to the Z axis is set to the X axis.

The results of a simulation performed by the inventor on the correlation between the phase of the rectangular voltage and the ion motion state (spatial distribution and velocity distribution) are explained below.

Figures 6 to 9 show the simulation results of the spread of ion positions in the X-axis direction (X) and the velocity in the X-axis direction (Vx) in the ion trap 31 when the phase of the rectangular voltage is 0°, 90°, 180°, and 270°, respectively. These results show that there is no significant change in the spread of ion positions in the X-axis direction even if the phase of the rectangular voltage applied to the ring electrode 311 is changed.

Figures 10 to 13 show the results of simulating the spread of ion positions in the Z-axis direction (Z) and the velocity in the Z-axis direction (Vz) in the ion trap 31 when the phase of the rectangular voltage is 0°, 90°, 180°, and 270°, respectively. Unlike the X-axis direction, these results show that the spread of ion positions in the Z-axis direction also changes when the phase of the rectangular voltage applied to the ring electrode 311 changes. Of these, it can be seen that the ions spread most elongated in the Z-axis direction and are most narrowly distributed in the X-axis direction when the phase is particularly 270°. Since the electron beam from the electron beam irradiation unit 30 is irradiated in the Z-axis direction (negative direction of the Z axis), if the electron beam is irradiated inside the ion trap 31 at this timing, the electron beam can be irradiated most efficiently to the ions captured in the ion trap 31. In other words, the spatial overlap between the ion cloud and the electron beam becomes large. Therefore, in this embodiment, the electron beam from the electron beam irradiation unit 30 is irradiated into the ion trap 31 around the timing when the phase of the rectangular voltage applied to the ring electrode 311 becomes 270° (the timing indicated by hatching in FIG. 4).

Furthermore, in the past, the electron beam was continuously irradiated onto the ions trapped in the ion trap, but the high-frequency sinusoidal voltage applied to the ring electrode changed over time, which caused the direction and magnitude of the electron beam deflection to change over time. As a result, the background that did not contribute to diffraction increased, making the electron beam diffraction image unclear.

In contrast, in the mass spectrometer 1 of this embodiment, a pulsed electron beam is irradiated at a timing around when the phase of the rectangular voltage is 270°. In other words, since the electric field formed inside the ion trap 31 at the timing of irradiating the electron beam is always the same, it is possible to consider in advance the effect that this electric field has on the path of the electron beam, and determine measurement conditions such as the irradiation direction of the electron beam to compensate for this.

The electron beam that passes through the ion trap 31 without being diffracted by the product ions is incident on the Faraday cup 321. A current corresponding to the amount of the incident electron beam is generated in the Faraday cup 321, and the amount of the electron beam irradiated from the electron beam irradiation unit 30 is estimated based on the magnitude of the current.

The electron beam diffracted by the product ions trapped in the ion trap 31 enters the microchannel plate 322. Electron multipliers are arranged two-dimensionally in the microchannel plate 322, and electrons entering the electron multipliers are amplified and emitted from the opposite side. The electrons emitted from the electron multipliers enter the fluorescent screen 323. A fluorescent material is applied to the surface of the fluorescent screen 323 in advance, and electrons entering the fluorescent screen 323 cause the fluorescent material to emit fluorescence at the position of incidence. A CCD camera 324 is arranged on the back side of the fluorescent screen 323, and captures the fluorescence emitted from the fluorescent screen 323 at a predetermined cycle and transmits the captured data sequentially to the control/processing unit 4. The control/processing unit 4 stores the received captured data in the memory unit 41.

When measurements for all time periods are completed, the analysis processing unit 45 reads out the MRM measurement data obtained for each compound. Then, the presence or absence of the compound is determined from the ion intensity in the MRM measurement. In addition, the compound is quantified as necessary. Compound quantification can be performed by storing calibration curve information for the target compound in advance and comparing the ion intensity in the MRM measurement with the calibration curve.

The analysis processing unit 45 reads out the data of the electron beam diffraction image acquired in time period 4. It also refers to the compound database 411 and reads out the data of the electron beam diffraction images of compounds C and D, which are the measurement targets in time period 4. At this time, if the data of the electron beam diffraction image of either compound C or D is not recorded in the compound database 411, the electron beam diffraction image estimation unit 46 theoretically estimates the electron beam diffraction image based on the molecular structure information of the compound (for example, estimating the molecular structure by first-principles calculations and theoretically determining the electron beam diffraction image from the contribution of each atom) and creates the electron beam diffraction image data.

Next, the analysis processing unit 45 compares the measurement data of the electron beam diffraction image obtained by the measurement with the data of the electron beam diffraction images of compounds C and D. Then, based on the degree of agreement between the two, it determines the presence or absence of compounds C and D (whether only compound C, only compound D, or both compounds C and D are included).

As an example, let us refer to FIG. 14 to explain the electron diffraction pattern of carbon tetrachloride (CCl ₄ ). In carbon tetrachloride, a carbon atom (C) and four chlorine atoms (Cl) are bonded with an interatomic distance r. When an electron beam is irradiated onto this, the electrons are scattered in various directions, but at a certain direction θ, the waves (de Broglie waves) of the electrons scattered from C and from Cl reinforce each other. On the other hand, at an angle θ', they cancel each other out. Since the orientation of the molecules is random, concentric fringes are formed on the detection surface due to interference. The radius of these concentric circles is related to the distance r, and the distance r can be obtained by comparing the theoretical interference fringes and the observed interference fringes when the distance r is changed as a parameter. In the case of carbon tetrachloride (CCl ₄ ), two peaks corresponding to the C-Cl equilibrium distance and the Cl-Cl equilibrium distance are obtained on the radial distribution function.

However, the number of atoms in compounds measured by liquid chromatography-mass spectrometry and other methods is generally greater than that of carbon tetrachloride. In the electron diffraction images of such compounds, peaks corresponding to interatomic distances overlap each other. For this reason, it is difficult to determine the interatomic distances of each bond within a molecule from the electron diffraction image alone.

In contrast, in this embodiment, since the mass-to-charge ratio of the ions can be known by first performing mass spectrometry, the functional groups contained in the molecular structure of the compound can be assumed based on the mass-to-charge ratio, and it is possible to estimate whether or not the functional group is contained based on the presence or absence of interference fringes specific to the functional group. In addition, for structural isomers, it is possible to estimate which of multiple structural isomers the measured compound is from the difference in interference fringes that appears due to the positional relationship between the functional group and the different positions in the molecular structures of the structural isomers.

Recently, the accuracy of molecular structures (the positions of each atom within a molecule) determined by first-principles calculations has improved, making it possible to estimate with high accuracy the interference fringes that appear in electron diffraction patterns from those molecular structures. By comparing electron diffraction patterns obtained from simulations based on these theoretical calculations with those obtained from actual measurements, it is possible to identify structural isomers and determine the proportions of mixtures of these isomers.

The mass spectrometer 1 of this embodiment can perform various measurements other than the above-mentioned example. In the above example, MRM measurement and electron diffraction measurement are combined, but product ion scan measurement and electron diffraction measurement can also be combined. For example, it is conceivable to first perform a product ion scan measurement on the compound to be measured to measure the product ion spectrum, and then perform electron diffraction measurement to analyze the structure of the ion corresponding to the peak that appears on the spectrum.

In the above example, precursor ions of a predetermined mass-to-charge ratio generated from a sample are dissociated in the collision cell 232 to generate product ions, which are then measured (mass spectrometry and electron diffraction measurements). However, it is also possible to not dissociate ions in the collision cell 232, but to measure ions that are generated from a sample and are mass-separated in the front-stage quadrupole mass filter 231 or rear-stage quadrupole mass filter 233 (mass spectrometry and electron diffraction measurements).

In the above example, electron beam diffraction was performed on compounds C and D, which are not separated by a liquid chromatograph column (they have the same retention time). However, even in the case of isomers that can be separated by a column, the liquid chromatograph column only separates the compounds and does not provide information on the molecular structure of the compounds. Therefore, by performing electron beam diffraction measurements as in the above example and also obtaining information on the molecular structure of the compounds, it is possible to analyze each compound separated by liquid chromatography with higher accuracy. In addition, in the above example, the mass spectrometer 1 of this embodiment can be combined with a gas chromatograph (GC) rather than a liquid chromatograph (LC) (Figure 15).

In addition, it is also possible to combine the mass spectrometer 1 of this embodiment with an ion mobility spectrometer (IMS) (Figure 16), or to perform measurements using an apparatus configured by combining, from the upstream side, a chromatograph (liquid chromatograph or gas chromatograph), an ion mobility spectrometer, and the mass spectrometer 1 of this embodiment (Figure 17).

In an ion mobility analyzer, ions are separated according to the size of the collision cross section of the ions, and it is said that it is possible to distinguish isomers. However, the theoretical value of the size of the collision cross section of the ions often does not match the actual value. In addition, the measured value of the collision cross section of the ions also varies depending on the configuration of the device (for example, by manufacturer) and the type of gas with which the ions are collided. Therefore, even if the size of the collision cross section of the ions obtained by measurement is compared with the value recorded in the database, it may not be possible to identify the molecular structure. In other words, as with a chromatographic device, even if a compound can be separated, information on the molecular structure of the compound cannot be obtained. As shown in Figures 16 and 17, by combining an ion mobility analyzer with the mass spectrometer 1 of this embodiment, not only the size of the collision cross section of the ions but also molecular structure information can be obtained by electron beam diffraction measurement, and the compounds contained in the sample can be analyzed with higher accuracy. When combining an ion mobility analyzer, the ionization section of the mass spectrometer 1 and other components (in the figure, the electron beam irradiation section and the like are described as the mass analysis section) are separated, and the ion mobility analysis section is placed between them.

As described above, concentric stripes appear in electron diffraction images due to the interference of electron waves (de Broglie waves), so by changing the wavelength, different electron diffraction images can be obtained from the same molecule. When the wavelength of the electron beam used in electron diffraction measurement is changed, the interatomic distance that reinforces the electron beam of that wavelength changes, resulting in differences in the observed interference fringes. In this method for determining the degree of agreement of the overall pattern of interference fringes, the energy of the incident electrons is an important parameter. Therefore, in the mass spectrometer 1 of this embodiment, when it is not possible to identify with sufficient accuracy which of the structural isomers the component contained in the sample is, for example, only by the measurement in the above example, the user can perform electron diffraction measurement by irradiating electron beams with different energies as the condition for the electron diffraction measurement through the measurement condition setting unit 43, and obtain multiple electron diffraction images by performing measurements using electron beams of multiple different wavelengths (multiple different energies) during measurement by the measurement control unit 44. After the measurement is completed, the second molecular structure estimation unit 472 analyzes the differences in the interference fringes that appear in the multiple electron beam diffraction images to estimate the molecular structure.

Electron beams are scattered by both atomic nuclei and electrons, but the number of atomic nuclei and electrons is greater in atoms with larger atomic numbers. In other words, the scattering intensity is greater for atoms with larger atomic numbers. Therefore, in the mass spectrometer 1 of this embodiment, a sample can be prepared in which atoms with larger atomic numbers (or functional groups containing atoms with larger atomic numbers) are added or substituted in advance at positions where the molecular structures differ between structural isomers or in the vicinity of those positions, and electron beam diffraction measurements can be performed using the sample. In this case, after the measurement is completed, the third molecular structure estimation unit 473 extracts interference fringes corresponding to the added atoms or functional groups from the electron beam diffraction image to estimate the molecular structure.

The above embodiment is merely an example and can be modified appropriately in accordance with the spirit of the present invention.
In the above embodiment, the ESI probe 201 is used as the ionization unit, but an ionization unit such as an atmospheric pressure chemical ionization device can be used. In addition, when measuring a gas sample, an electron ionization device or a chemical ionization device can also be used.

In the above example, a triple quadrupole type mass analyzer was used, but other mass analyzers, such as quadrupole time-of-flight type, can be used. In addition, when using an ionization unit that produces fragment ions during ionization, such as an electron ionizer, a mass analyzer with only one mass separation unit (for example, with only one quadrupole mass filter) may be used.

In the above embodiment, the deflection unit 236 is provided, but the deflection unit 236 may not be used. For example, the configuration may be as shown in the block diagram of FIG. 18. In this configuration, when performing mass analysis (solid line), no voltage is applied to the ion trap, and ions that have been mass-separated in the mass analysis unit are passed through the ion trap and detected by the ion detector. When performing electron beam diffraction measurement (dashed line), a voltage is applied to the ion trap to accumulate ions, an electron beam is irradiated from the electron beam irradiation unit, and the diffraction image is obtained by the electron beam detection unit.

The mass spectrometer 1 in the above embodiment is also configured to perform electron beam diffraction to obtain information on molecular structure, but based on a similar concept, it is also possible to configure a mass spectrometer that is also configured to perform rotational spectrum measurement and X-ray diffraction measurement.

NMR is sometimes used to estimate molecular structure, but the sensitivity of NMR is significantly lower than that of mass spectrometry, by more than two orders of magnitude, so when measuring the same sample, a separate sample must be prepared in which the components to be measured are more concentrated than the sample used for mass spectrometry. Some samples are difficult to synthesize or prepare, and furthermore, product ions as described above cannot be measured. Furthermore, the measurement itself must be performed separately from mass spectrometry. In contrast, the mass spectrometer of the above embodiment can perform both mass spectrometry and electron beam diffraction measurement simultaneously and with high sensitivity in a single measurement sequence.

In the above examples and modifications, electron diffraction measurements were performed in addition to mass analysis, but various secondary measurements can be performed in addition to electron diffraction measurements. In the present invention, after mass separation, only ions having a specific mass-to-charge ratio (or a mass-to-charge ratio within a specific range of mass-to-charge ratios) are captured in the ion trap as ions to be measured, and various physical quantities related to the ions to be measured can be measured (physical property information can be obtained).

Figure 19 shows a measurement method (including the electron beam diffraction measurement in the above embodiment) in which an electromagnetic wave (light beam, etc.) or a particle beam is incident on an ion trap, and the electromagnetic wave (light, etc.) or particle emitted from the ion trap is detected after interacting with the ion trapped in the ion trap (trapped ion) as an example of a secondary measurement that can be performed in the mass spectrometer according to the present invention. Here, in the case of incident electromagnetic waves, examples of the interaction include absorption or scattering of the electromagnetic wave by the trapped ions. Ions that have absorbed electromagnetic waves and transitioned to an excited state return to the ground state by emitting electromagnetic waves with a wavelength different from that of the incident electromagnetic wave or emitting a particle beam. In addition, electromagnetic waves may not be absorbed by ions and may undergo elastic or inelastic scattering (including diffraction). In the case of incident particle beams, scattering may be an example of an interaction with the trapped ions. Ions that have obtained energy from the incident particles and transitioned to an excited state return to the ground state by emitting electromagnetic waves or emitting a particle beam. In addition, incident particles may undergo elastic or inelastic scattering (including diffraction). Other examples of secondary measurements include a measurement method in which an electromagnetic wave (such as a light beam) or a particle beam is incident on an ion trap and the electromagnetic wave (such as a light beam) or particle that exits the ion trap is detected without interacting with the trapped ions. In absorbance measurements, electromagnetic waves that pass through the ion trap without interacting with the trapped ions are detected. Secondary measurements can also include comparing the differences in measurement results when different ion species are trapped.

Examples of device configurations that can be used in common for these are shown in Figures 20 and 21. Figure 20 shows a configuration with a deflection unit, as in the above embodiment, and Figure 21 shows a configuration without a deflection unit, as in the above modified example. In Figures 20 and 21, solid lines indicate components for performing mass analysis, and dashed lines indicate components for performing secondary measurements.

For example, information on the molecular structure of the ion can be obtained by performing electron beam diffraction measurement by irradiating the trapped ion with an electron beam and measuring the electrons diffracted by the ion. Information on the electronic state of the ion can be obtained by performing electron energy loss spectroscopy by irradiating the trapped ion with an electron beam to excite it and measuring the electrons scattered by the ion. In addition, the electronic structure analysis and elemental analysis of the ion can be performed by using the device as an electron beam microprobe analyzer (EPMA) that irradiates the trapped ion with an electron beam to excite it and measures the light emitted from the ion. In addition, elemental analysis can be performed by performing ion scattering spectroscopy by irradiating the trapped ion with a beam of ions other than the ion (ion beam) to excite it and detecting the ions scattered by the ion. In addition, elemental analysis can be performed by performing particle induced fluorescence spectroscopy by irradiating the trapped ion with an ion beam to excite it and detecting the light emitted from the ion. In addition, elemental analysis can be performed by performing atomic absorption spectroscopy by irradiating the trapped ion with a light beam to excite it and detecting the light emitted from the ion. In addition, by irradiating the trapped ion with light and detecting the light diffracted by the ion, information on the shape and molecular structure of the ion can be obtained by performing laser diffraction measurement or X-ray diffraction measurement. In addition, by irradiating the trapped ion with light and detecting the light transmitted through the ion, the amount of light absorbed by the ion can be measured by X-ray absorption edge measurement or Fourier transform infrared spectroscopy, information on the intramolecular bond of the ion can be obtained. In addition, by irradiating the trapped ion with light and detecting the light scattered by the ion, Raman spectroscopy can be performed to obtain information on the intramolecular bond of the ion. In addition, by irradiating the trapped ion with light and performing photoelectron spectroscopy to measure the electrons released from the ion, information on the electronic state and bonding state of the ion can also be obtained.

[Aspects]
It will be appreciated by those skilled in the art that the exemplary embodiments described above are examples of the following aspects.

(Section 1)
A mass spectrometer according to one embodiment comprises:
an ionization unit for generating ions from a sample;
a mass separation unit that separates the ions generated in the ionization unit according to their mass-to-charge ratio ;
an ion detector that detects ions separated by the mass separation unit;
an ion trapping unit that traps the ions separated by the mass separation unit;
and a sub-measurement unit that measures a physical quantity of the ions trapped in the ion trapping unit other than the mass-to-charge ratio.

In the mass spectrometer of the first paragraph, mass analysis can be performed by mass-separating the ions generated in the ionization section in the mass separation section and detecting them with an ion detector. In addition, after mass-separating the ions generated in the ionization section in the mass separation section to select the ions to be analyzed, they can be captured in the ion trapping section and physical quantities other than the mass-to-charge ratio can be measured (secondary measurement). The secondary measurement can be, for example, irradiating the ions captured in the ion trapping section with an electromagnetic wave (light beam, etc.) or a particle beam, and detecting the electromagnetic wave (light, etc.) or particles emitted from the ion trapping section. Specifically, for example, after accumulating the ions to be analyzed in the ion trapping section, an electron beam can be irradiated thereon for a predetermined time, and the electron beam diffracted by the ions in the ion trapping section can be detected to perform electron beam diffraction measurement. Although mass analysis alone cannot distinguish isomers with the same mass-to-charge ratio, the mass spectrometer of the first paragraph can obtain information on the molecular structure and distinguish isomers, for example, by performing the above-mentioned electron beam diffraction measurement as a secondary measurement. In addition, in the mass spectrometer of paragraph 1, by appropriately changing the flight path of the ions, it is possible to perform both mass analysis, which separates and detects the ions generated in the ionization section, and secondary measurement, which captures the ions after the mass separation and measures physical quantities other than the mass-to-charge ratio of the ions, in a single measurement.

If mass separation is performed in an ion trapping section (typically a three-dimensional ion trap) with an excessive amount of ions trapped in the ion trapping section, the electric field inside the ion trapping section is distorted by the charge (space charge) of the ions themselves, making it impossible to perform normal mass separation. In addition, in the conventionally proposed devices, ions generated from a sample are introduced into the ion trapping section, and ions to be analyzed are selected in the ion trapping section, so that the amount of ions that can be captured in the ion trapping section is limited. Even if the maximum amount of ions is captured at the initial point, the amount of ions to be analyzed contained therein is less than the maximum amount. In contrast, in the mass spectrometer of paragraph 1, ions to be analyzed are selected by a mass separation section outside the ion trapping section, and only the ions to be analyzed are introduced into the ion trapping section, so that the maximum amount of ions to be analyzed can be captured and used for electron beam diffraction measurement, and a diffraction image with high intensity can be obtained more efficiently than in the past.

(Section 2)
2. The mass spectrometer according to claim 1,
The mass separation unit is
a mass pre-separation section for selecting ions having a specific mass-to-charge ratio as precursor ions from the ions generated in the ionization section;
a dissociation unit that dissociates the precursor ions to generate product ions;
a post-mass separation section that selects ions having a specific mass-to-charge ratio from the product ions.

The mass spectrometer described in paragraph 2 can perform mass analysis using ions characteristic of the compound to be measured by selecting precursor ions and product ions in the front-stage mass separation section and rear-stage mass separation section, respectively, or perform electron beam diffraction measurement by selecting product ions having local partial structures including positions of different molecular structures of structural isomers.

(Section 3)
The mass spectrometer according to claim 1 or 2, further comprising:
a deflection unit provided between the mass separation unit and the ion detector, the deflection unit deflecting a flight direction of the ions emitted from the mass separation unit,
The ion trapping section is provided on a flight path of the ions whose flight direction has been deflected by the deflection section.

In the mass spectrometer described in paragraph 3, ions separated in the mass separation section are deflected and introduced into the ion trapping section, so that the ions are separated from the neutral molecules and only the ions to be analyzed are introduced into the ion trapping section, thereby reducing the background of the electron diffraction image caused by the scattering of electrons by neutral molecules. In addition, in the mass spectrometer described in paragraph 3, ions having a predetermined mass-to-charge ratio generated from the sample are captured in the ion trapping section, and an electron beam is irradiated thereon to perform electron diffraction measurement, while at the same time performing mass analysis of new ions generated in the ionization section.

(Section 4)
4. The mass spectrometer according to claim 1, further comprising:
The ion trapping portion includes a voltage application portion that applies a square wave voltage to the ion trapping portion to trap ions.

The mass spectrometer described in paragraph 4 can change the mass-to-charge ratio (range) of the ions captured in the ion trapping section by changing the frequency while keeping the amplitude of the square wave voltage constant, so no large power supply is required. In addition, there is no need to worry about discharges caused by the application of high voltage or deflection of the flight path of the electron beam.

(Section 5)
5. The mass spectrometer according to claim 1, wherein the sub-measurement unit comprises:
an irradiation unit that irradiates the ions trapped in the ion trapping unit with an electromagnetic wave or a particle beam;
and a detection unit that detects electromagnetic waves or particles emitted from the ion trapping unit.

The mass spectrometer of the fifth paragraph can perform various measurements as described below. For example, the ions captured in the ion trapping section (trapped ions) can be irradiated with an electron beam and the electron beam diffracted by the ions can be measured to perform electron beam diffraction measurement, thereby obtaining information on the molecular structure of the ions. In addition, the trapped ions can be excited by irradiating them with an electron beam, and the electrons scattered by the ions can be measured to perform electron energy loss spectroscopy, thereby obtaining information on the electronic state of the ions. In addition, the trapped ions can be excited by irradiating them with an electron beam, and the device can be used as an electron beam microprobe analyzer (EPMA) that measures the light emitted from the ions, thereby performing electronic structure analysis and elemental analysis of the ions. Furthermore, the trapped ions can be excited by irradiating them with an ion beam, and the ions scattered by the ions can be detected to perform ion scattering spectroscopy to perform elemental analysis. Alternatively, the trapped ions can be excited by irradiating them with an ion beam, and the light emitted from the ions can be detected to perform particle -induced fluorescence spectroscopy to perform elemental analysis. In addition, the trapped ions can be excited by irradiating them with a light beam, and the light emitted from the ions can be detected to perform atomic absorption spectroscopy to perform elemental analysis. In addition, by irradiating the trapped ion with light and detecting the light diffracted by the ion, information on the shape and molecular structure of the ion can be obtained by performing laser diffraction measurement or X-ray diffraction measurement. In addition, by irradiating the trapped ion with light and detecting the light transmitted through the ion, the amount of light absorbed by the ion can be measured by X-ray absorption edge measurement or Fourier transform infrared spectroscopy, information on the intramolecular bond of the ion can be obtained. In addition, by irradiating the trapped ion with light and detecting the light scattered by the ion, Raman spectroscopy can be performed to obtain information on the intramolecular bond of the ion. In addition, by irradiating the trapped ion with light and performing photoelectron spectroscopy to measure the electrons released from the ion, information on the electronic state and bonding state of the ion can also be obtained.

(Section 6)
4. The mass spectrometer according to claim 1, further comprising:
A voltage application unit that applies a square wave voltage to the ion trapping unit to trap ions.
Equipped with
The sub-measurement unit,
an irradiation unit that irradiates the ions trapped in the ion trapping unit with an electromagnetic wave or a particle beam;
a detection unit for detecting electromagnetic waves or particles emitted from the ion capture unit;
Equipped with
When a rectangular wave voltage of a predetermined phase is applied from the voltage application unit to the ion-trapping unit, the irradiation unit irradiates the inside of the ion-trapping unit with a pulsed electromagnetic wave or particles.

In the mass spectrometer described in paragraph 5, by performing simulations or preliminary experiments in advance, the phase of the square wave voltage that causes ions to spread along the irradiation path of the electromagnetic wave or particle beam in the ion trapping section is determined as the above-mentioned predetermined phase, so that more ions can be irradiated with the electromagnetic wave or particle beam and a high signal intensity can be obtained. In a mass spectrometer configured to apply a high frequency sine voltage to a ring electrode to trap ions inside an ion trap as in the past, a phase difference occurs between the voltage that drives the resonant circuit and the output voltage of the resonant circuit that is actually applied to the electrode. This depends on the load impedance of the electrode and varies depending on the electrode shape and the method of holding it. Therefore, it is difficult to irradiate the electromagnetic wave or particle beam at the moment when the high frequency sine voltage reaches a specific phase. Even if the phase can be adjusted, the amplitude of the high frequency sine voltage needs to be changed according to the mass-to-charge ratio of the ions to be measured, and the voltage setting value of the entrance optical system for the electromagnetic wave or particle beam needs to be changed accordingly. In contrast, in the mass spectrometer described in paragraph 5, the drive voltage is applied directly to the electrodes without going through a resonant circuit, so that the electromagnetic waves or particle beams can be controlled to be irradiated in accordance with the optimal phase. Furthermore, even if the mass-to-charge ratio of the ions to be measured changes, only the frequency of the square wave voltage changes, and the amplitude remains constant, so there is no need to change the voltage setting value of the incidence optical system for the electromagnetic waves or particle beams.

(Section 7)
7. The mass spectrometer according to claim 5 or 6,
the irradiation unit is an electron beam irradiation unit that irradiates the ion trapping unit with an electron beam,
The detection unit detects the electron beam diffracted by the ions.

The mass spectrometer described in paragraph 7 can perform electron diffraction measurements on ions of a specific mass-to-charge ratio (or mass-to-charge ratio range) captured in the ion trapping section to obtain information on the molecular structure of the ions.

(Section 8)
8. The mass spectrometer according to claim 7, further comprising:
a molecular structure candidate input receiving unit that receives input of information on the molecular structure candidate;
and a first molecular structure estimation unit that estimates the molecular structure of a molecule contained in the sample by comparing an electron beam diffraction image obtained by measuring the sample with an electron beam diffraction image prepared in advance for the molecular structure candidate.

In the mass spectrometer described in paragraph 8, the electron beam diffraction image obtained by measurement can be analyzed more easily by using a previously prepared electron beam diffraction image (for example, an electron beam diffraction image obtained by electron beam diffraction of a standard sample or an electron beam diffraction image estimated based on theoretical calculation as described in the next paragraph). In addition, in the mass spectrometer described in paragraph 7 , unlike the diffraction peaks obtained by general electron beam diffraction measurement, data of concentric interference fringes is obtained as a diffraction image. Such data can be processed as a type of image data. Therefore, as the first molecular structure estimation unit, for example, a classifier created by machine learning the entire pattern of the diffraction images obtained by electron beam diffraction measurement and/or theoretical calculation of various compounds can be used.

(Section 9)
9. The mass spectrometer according to claim 8, further comprising:
and an electron beam diffraction image estimating unit that estimates an electron beam diffraction image by theoretical calculation based on the molecular structure accepted by the molecular structure candidate input accepting unit.

The mass spectrometer described in paragraph 9 can estimate electron beam diffraction patterns for compounds that are not included in the compound database.

(Article 10)
10. The mass spectrometer according to any one of claims 7 to 9,
The energy of the electron beam irradiated by the electron beam irradiating unit is variable.

(Article 11)
11. The mass spectrometer according to claim 10, further comprising:
The second molecular structure estimation unit estimates the structure of the sample molecule based on electron beam diffraction images obtained by irradiating the sample with electron beams of different energies.

The mass spectrometer described in paragraphs 10 and 11 performs electron diffraction measurements using electron beams of different energies, thereby obtaining different electron diffraction images for the same molecule and using them to analyze the molecular structure.

(Article 12)
12. The mass spectrometer according to any one of claims 7 to 11, further comprising:
The apparatus further includes a third molecular structure estimation unit that estimates the molecular structure of a sample molecule based on an electron beam diffraction image obtained by measuring a compound in which a predetermined type of atom is bonded to a specific position of the sample molecule.

In the mass spectrometer described in paragraph 12, atoms with a large atomic number that scatters more electrons are added as the above-mentioned predetermined type of atom to a position of interest in the molecule (for example, a position where the structure differs between isomers or in the vicinity thereof), thereby increasing the scattering of the electron beam by the atom, and making it possible to obtain high-intensity interference fringes that reflect the structure of interest.

(Article 13)
13. The mass spectrometer according to any one of claims 1 to 12, further comprising:
The mass separation section includes a separation means for separating compounds contained in the sample before the ions are mass-separated in the mass separation section.

(Article 14)
14. The mass spectrometer according to claim 13,
The separation means is a chromatographic device and/or an ion mobility spectrometer.

In the mass spectrometer described in paragraph 13, the compounds contained in the sample are separated from each other and introduced into the ion source, so that only the compounds to be measured are selected, and the influence of other compounds is eliminated, allowing mass analysis and electron beam diffraction measurement to be performed with higher accuracy. As such a separation means, as described in paragraph 14, a chromatograph (for example, a liquid chromatograph or a gas chromatograph) or an ion mobility analyzer can be used. When the separation means is a chromatograph, the compounds contained in the sample are separated, and then each compound is introduced into the ionization section for ionization. In this case, the separation means is disposed in the front stage of the mass spectrometer. On the other hand, when the separation means is an ion mobility analyzer, the compounds contained in the sample are ionized in the ionization section, and then ions derived from each compound are separated in the ion mobility analyzer and introduced into the mass separation section. In this case, the separation means is disposed between the ionization section and the mass separation section of the mass spectrometer. In this way, the separation of the above compounds also includes a configuration for separating ions derived from each compound.

Depending on the type of isomer, it may be possible to separate them using a chromatographic column, but since it is not possible to obtain information about the compound's molecular structure through separation using a chromatographic device alone, it is necessary to also perform electron diffraction measurements to obtain information about the compound's molecular structure, allowing the compounds contained in the sample to be analyzed with greater precision.

In addition, although it is said that the ion mobility analyzer can distinguish isomers, the theoretical value of the collision cross section of the ion and the actual measured value do not often match, and the measured value of the collision cross section also varies depending on the configuration of the device (e.g., by manufacturer) and the type of gas with which the ions collide. Therefore, it is difficult to compare the collision cross section of the ion obtained by measurement with the value recorded in the database, and it may not be possible to identify the molecular structure. By combining the ion mobility analyzer with the mass spectrometer of the present invention , not only the collision cross section of the ion but also molecular structure information can be obtained by electron beam diffraction measurement, and the compounds contained in the sample can be analyzed with higher accuracy.

Reference Signs List 1: Mass spectrometer 10: Apparatus body 20: Ionization chamber 21: First intermediate vacuum chamber 22: Second intermediate vacuum chamber 23: Analysis chamber 231: Front quadrupole mass filter 232: Collision cell 234: Quadrupole rod electrode 235: Rear quadrupole mass filter 236: Deflection section 2361: Rod electrode 237: Ion detector 30: Electron beam irradiation section 301: Electron gun 302: Electron lens 31: Ion trap 311: Ring electrode
312: inlet end cap electrode 313: outlet end cap electrode 316: vacuum chamber 317: gas inlet 32: electron beam detector 321: Faraday cup 322: microchannel plate
323 ... Fluorescent screen 324... CCD camera 4... Control/processing unit 41... Memory unit 411... Compound database 42... Mass analysis program 43... Measurement condition setting unit 44... Measurement control unit 45... Analysis processing unit 46... Electron beam diffraction image estimation unit 47... Molecular structure estimation unit 471... First molecular structure estimation unit 472... Second molecular structure estimation unit 473... Third molecular structure estimation unit 5... Voltage application unit 6... Input unit 7... Display unit

Claims (13)

an ionization unit for generating ions from a sample;
a mass separation unit that separates the ions generated in the ionization unit according to their mass-to-charge ratio;
an ion detector that detects ions separated by the mass separation unit;
an ion trapping unit that traps the ions separated by the mass separation unit;
a sub-measurement unit for measuring a physical quantity of the ions trapped in the ion trapping unit other than the mass-to-charge ratio;
Equipped with
The mass separation unit is
a mass pre-separation section for selecting ions having a specific mass-to-charge ratio as precursor ions from the ions generated in the ionization section;
a dissociation unit that dissociates the precursor ions to generate product ions;
a post-stage mass separator for selecting ions having a specific mass-to-charge ratio from among the product ions;
A mass spectrometer comprising: moreover,
a deflection unit provided between the mass separation unit and the ion detector, the deflection unit deflecting a flight direction of the ions emitted from the mass separation unit,
2. The mass spectrometer according to claim 1 , wherein the ion trapping section is provided on a flight path of ions whose flight direction has been deflected by the deflection section. moreover,
The mass spectrometer according to claim 1 , further comprising a voltage application unit that applies a square wave voltage to the ion trapping unit to trap ions. The sub-measurement unit,
an irradiation unit that irradiates the ions trapped in the ion trapping unit with an electromagnetic wave or a particle beam;
The mass spectrometer according to claim 1 , further comprising: a detection unit that detects electromagnetic waves or particles emitted from the ion trapping unit. an ionization unit for generating ions from a sample;
a mass separation unit that separates the ions generated in the ionization unit according to their mass-to-charge ratio;
an ion detector that detects ions separated by the mass separation unit;
an ion trapping unit that traps the ions separated by the mass separation unit;
a sub-measurement unit for measuring a physical quantity of the ions trapped in the ion trapping unit other than the mass-to-charge ratio;
a voltage application unit that applies a square wave voltage to the ion trapping unit to trap ions;
Equipped with
The sub-measurement unit,
an irradiation unit that irradiates the ions trapped in the ion trapping unit with an electromagnetic wave or a particle beam;
a detection unit that detects electromagnetic waves or particles emitted from the ion trapping unit,
A mass spectrometer, wherein when a rectangular wave voltage of a predetermined phase is applied from the voltage application unit to the ion trapping unit, the irradiation unit irradiates an inside of the ion trapping unit with a pulsed electromagnetic wave or particle beam. the irradiation unit is an electron beam irradiation unit that irradiates the ion trapping unit with an electron beam,
6. The mass spectrometer according to claim 4 , wherein the detection section detects an electron beam diffracted by the ions. moreover,
a molecular structure candidate input receiving unit that receives input of information on the molecular structure candidate;
and a first molecular structure estimation unit that estimates a molecular structure of a molecule contained in the sample by comparing an electron beam diffraction image obtained by measuring the sample with an electron beam diffraction image previously prepared for the molecular structure candidate. moreover,
8. The mass spectrometer according to claim 7 , further comprising: an electron beam diffraction image estimating unit that estimates an electron beam diffraction image by theoretical calculation based on the molecular structure accepted by the molecular structure candidate input accepting unit. 9. The mass spectrometer according to claim 6 , wherein the energy of the electron beam irradiated by the electron beam irradiating unit is variable. moreover,
The mass spectrometer according to claim 9 , further comprising: a second molecular structure estimation unit that estimates a structure of a sample molecule based on an electron beam diffraction image obtained by irradiating the sample with electron beams of different energies. moreover,
11. The mass spectrometer according to claim 6, further comprising: a third molecular structure estimation unit that estimates a molecular structure of the sample molecule based on an electron beam diffraction image obtained by measuring a compound in which a predetermined type of atom is bonded to a specific position of the sample molecule. moreover,
The mass spectrometer according to claim 1 , further comprising: a separation unit that separates compounds contained in the sample before mass-separating ions in the mass separation section. 13. A mass spectrometer as claimed in claim 12 , wherein the separation means is a chromatographic device and/or an ion mobility spectrometer.

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