1. Field of the Invention
This invention relates to time-of-flight mass spectrometers that incorporate an ion mirror or reflector to increase the effective length of the drift region focusing. More particularly it relates to such spectrometers having more than one ion reflector and in which the number of reflections undergone by the ion packets can be varied to adjust the resolution of the spectrometer.
2. Discussion of the Prior Art
In a time-of-flight-mass spectrometer, mass-to-charge ratio of an ion is determined by accelerating it through to a given energy by means of an electrostatic field and measuring its subsequent flight time through a field-free drift region. The mass resolution of such a spectrometer is obviously dependent on the length of the drift region, because increasing its length will increase the separation in time between ions of adjacent mass-to-charge ratios. However, drift region length is in practice limited by the physical size of the spectrometer and certain observations, discussed below, limit the maximum resolution obtainable, irrespective of the drift region length. The two most important aberrations arise from:
1) variations in the position in the accelerating field at which the ion is generated; and
2) variations in the velocity imparted to the ion during its creation.
The first of these aberrations may be at least in part corrected by the space focusing technique, first taught by Wiley and McLaren in Rev. Sci. Instrum. 1955 vol 26 (12) pp 1150-1157, and in many subsequent papers and patents. The second aberration requires to be corrected by velocity focusing. The technique known as delayed extraction, also first suggested by Wiley and McLaren (ibid.) is a commonly used method of providing some degree of velocity focusing.
Another way of reducing the effect of different initial ion velocities is to provide an ion reflector at the end of the drift region to reflect the ions back towards the source through the drift region to a detector located close to the source. (See, for example, Mamyrin, Karatev et al, Sov. Phys. JETP, 1973, vol 37 (1) pp 45-48). Ions that leave the source region with a high velocity in the direction of the drift region will penetrate further into the ion reflector before being turned around than will ions of a lower initial velocity.
Consequently, ions with high initial velocity will travel a greater distance between the source and the detector than will ions of lower initial velocity. It is therefore possible to arrange the instrumental parameters so that the xe2x80x9cinitially fastxe2x80x9d and the xe2x80x9cinitially slowxe2x80x9d ions arrive at the detector at the same time.
Another advantage that results from the use of a reflecting analyser is that the distance travelled by the ions in the drift region is approximately double that it would be in a linear analyser of the same physical size, which results in improved resolution.
By the provision of multiple reflectors, it is possible to reduce the physical size of a reflection time-of-flight mass spectrometer still further merely by reflecting the ion packets backwards and forwards along a short drift region. However, each reflection results in a transmission loss (typically between 10% and 50%), and mass peaks tend to be broadened (and therefore reduced in intensity) as the path length is increased.
Several different versions of prior multiple-reflection time-of-flight mass spectrometers are known. That described by Chen and Su in Hezi Kexue (Nucl. Sci. J) 1991, vol 28 (3) pp 183-189 is a spectrometer having two parallel ion mirrors which reflect the ion packets a fixed number of times before they pass beyond the edge of one mirror to be received by an ion detector.
The spectrometers described in DE4418489, and U.S. Pat. No. 5,880,466 are essentially ion traps in which a packet of ions is repeatedly reflected between two parallel ion mirrors and does not enter a conventional ion detector. Instead, the oscillating ion packet is caused to induce a signal in sensing electrodes, which signal can be measured and processed by suitable electronic data processing equipment. GB 2080021 discloses in its FIG. 6 embodiment a multiple reflection time-of-flight mass spectrometer comprising an ion mirror that can be electronically tilted to reflect the incoming ion packets at different angles. At one such angle, the reflected packets pass into an ion detector, thereby enabling a moderate resolution spectrum to be recorded. At another such angle the reflected packets are directed to a second ion mirror and then to another ion detector, thereby providing increased path length and enabling a higher resolution spectrum to be recorded at lower sensitivity.
Multiple-reflection time-of-flight mass spectrometers incorporating switchable ion mirrors are taught by Wollnik and Przewloka in Int. J. Mass Spectrorn. and Ion Proc. 1990 vol 96 pp 267-274. The potentials applied to these mirrors can be switched off so that instead of being reflected, ion packets merely pass through the mirror undeflected, typically to an ion detector. Various configurations may be used in conjunction with suitable electronic timing and control circuiting to provide spectrometers with different path lengths.
Soviet Inventors Certificate SU 1725289 teaches a multiple-reflection spectrometer in which the ion source and the detector can be physically moved along an axis midway between the two reflectors. The distance between the source and detector controls the number of reflections of the ion packets and hence the resolution of the spectrometer. Piyadasa, Hakansson et. al. in Rapid Comm. in Mass Spectrom, 1999 vol 13 pp 620-624 describe a multiple reflection time-of-flight mass spectrometer in which two parallel ion mirrors are used to trap the ions, in a manner similar to that taught in U.S. Pat. No. 5,880,466. However, Piyadasa detects the ions by switching off one of the mirrors after a predetermined time to allow the ion packets to pass through the mirror and impact on a conventional ion detector. In this device, the number of ion reflections may be varied by adjustment of the time interval between the generation of an ion packet and the moment the ion mirror is switched off.
Hohl, Wurz, Scherer et.al. in Int. J. Mass Spectrom. 1999 vol 188 pp189-197 describe an instrument comprising two ion mirrors, the second of which is disposed between the ion source and the detector. In the xe2x80x9ctriple reflectionxe2x80x9d mode, ion packets pass from the source to the first mirror where they are reflected towards the second mirror. The second mirror returns them to the first mirror, which in turn reflects them to the ion detector. An electrostatic lens is located at the entrance of the first mirror. When a relatively low potential is applied to this lens, the spectrometer operates in a single-reflection mode wherein ion packets entering the first ion mirror are reflected directly into the ion detector. A higher potential applied to the lens results in the reflected ion packets being reflected by the second mirror so that the spectrometer operates in the triple reflection mode. These prior switchable mode spectrometers all require additional components such as lenses, power supplies and/or ion detectors.
It is an object of the present invention to provide a switchable mode multi-reflection time-of-flight mass spectrometer which is capable of at least first order velocity focusing in both single and multi-reflection modes and which requires fewer additional components than prior types. It is another object of the present invention to provide a time-of-flight mass analyzer having variable resolution into which ions are orthogonally injected. It is a further objective to provide a reflecting time-of-flight mass analyzer having orthogonal ion injection in which the resolution may be selected by varying the number of reflections undergone by the ions. Another objective is to provide such a time-of-flight mass analyzer in which the number of reflections can be changed more easily than is possible with prior multiple-reflection spectrometers. Other objectives are to provide mass spectrometers and tandem mass spectrometers comprising such time-of-flight mass analyzers. Another objective is to provide methods of changing the number of reflections in a time-of-flight mass analyzer having orthogonal ion injection, which are simpler and more easily implemented than prior methods. Further objectives are to provide methods of changing the resolution of a time-of-flight mass analyzer having orthogonal ion injection or of a mass spectrometer incorporating such an analyzer, which are simpler and more easily implemented than prior methods.
In accordance with these objectives the invention provides a time-of-flight mass analyzer comprising:
1) a drift region while travelling through which ions may be temporally separated according to their mass-to-charge ratios, said drift region having an axis, an entrance and an exit;
2) an ion packet generator for injecting packets of ions into said drift region at said entrance from a beam of ions by the intermittent application of an electrostatic field such that said packets of ions enter said drift region in an initial direction which is inclined to the direction of said beam of ions;
3) a first ion reflector disposed at said exit to reflect back towards said entrance ions which are travelling towards it in said drift region;
4) a second ion reflector disposed in juxtaposition to said first ion reflector to reflect those of said packets of ions which enter it back towards said first ion reflector through at least a portion of said drift region, so that packets of ions may be reflected to and fro between said first and said second ion reflectors and undergo a number n of reflections at said second ion reflector;
5) at least one ion detector disposed to detect at least some packets of ions reflected by said first ion reflector which do not enter said second ion reflector;
said time-of-flight analyzer characterized in that the number n of reflections at said second ion reflector is selected by adjustment of the inclination of said initial direction to said axis. In a preferred embodiment, the ion detector is disposed in a common plane with the ion packet generator at the entrance to the drift region. Preferably, this plane is perpendicular to the axis of the drift region. In still further preferred embodiments, the second ion reflector is disposed between the ion detector and the ion packet generator in another plane which is also perpendicular to the axis of the drift region. Most preferably, the two planes are coincident.
In a time-of-flight analyzer according to the invention, the length of the path travelled by the packets of ions from the ion packet generator to the ion detector is determined by the value of n. If n is zero, the analyzer functions as a conventional reflectron analyzer in which ion packets are generated by the ion packet generator and travel through the drift region to the first ion reflector. The first ion reflector then reflects them back through the drift region into the ion detector. An analyzer according to the invention may operate in this mode if the inclination of the initial direction to the drift region axis is such that the ions reflected by the first ion reflector do not enter the second ion reflector, but instead pass directly into the ion detector.
If, however, the inclination of the initial direction to the drift region axis is such that n=1 then ions leaving the ion packet generator travel through the drift region to the first ion reflector where they are reflected back through at least a portion of the drift region and enter the second ion reflector. This returns them to the first ion reflector, which in turn reflects them back through the drift region. By the time they reach the entrance of the drift region, however, their displacement from the drift region axis is now greater than it was after the first reflection at the first ion reflector so that they now enter the ion detector instead of the second ion reflector. (This mode of operation is described in greater detail below). When n=1, therefore, each packet of ions makes four passes through the drift region, in contrast to the conventional mode (n=0), in which they make only two. Consequently, a higher mass resolution can be achieved in the n=1 mode than in the n=0 mode because the distance travelled by the ions is twice as great. Unfortunately the increase in resolution is accompanied by a loss in sensitivity, however, because each reflection results in some loss of ions, sometimes as much as 50%.
It is also possible to operate an analyzer according to the invention with values of n=2 or higher. This is done by using lower angles of inclination between the initial direction and the drift region axis so that six (n=2) or more passes through the drift region are necessary before the displacement of the ion packets from the axis becomes sufficiently great for them to miss the second ion reflector and instead enter the ion detector. Each increase in the number of passes results in a higher mass resolution but with a further loss in sensitivity, as explained.
Preferred embodiments of the invention therefore comprise a time-of-flight analyzer which has at least two of these modes of operation, corresponding to at least a low resolution/high sensitivity mode and a high resolution/low sensitivity mode. (ie, a mode with a zero or low value of n, and a mode with a higher value of n). Means are provided for selecting the modes by changing the inclination of the initial direction at which the ions enter the drift region relative to its axis.
In a most preferred embodiment, the injection of ions into the drift region is done by intermittently applying an electrostatic field approximately orthogonally to the direction of travel of the beam of ions travelling through the ion packet generator, as in a conventional orthogonal acceleration time-of-flight mass analyser. Application of this field ejects a packet of ions comprising a segment of the ion beam into the drift region in an initial direction which is the resultant of the orthogonal velocity imparted to the ions by the field and their original transverse velocity through the ion packet generator. The orthogonal component of velocity is typically much greater than their original velocity so that the packet of ions leaves the ion packet generator in the approximate direction of the axis of the drift region, as in a prior orthogonal time-of-flight analyzer. As explained, the initial direction of travel in the drift region and the axis of the drift region determines the mode of operation of the analyzer. A high angle of inclination between the actual initial direction and the axis of the drift region results in a low (or zero) value of n, while a low angle gives a higher value of n. It will be appreciated that the initial direction, and consequently the value of n with which the time-of-flight analyzer operates, is determined by the ratio of the initial velocity of the ions as they enter the ion packet generator to the orthogonal velocity imparted to them in the ion packet generator. Further, because the velocity v of an ion is given by                     v        =                                            2              ⁢              E                        m                                              (        1        )            
where E is the kinetic energy of the ion and m is its mass, the ratio of the kinetic energies E, resolved into directions corresponding to the two components of velocity, also determines the angle at which the ion packets enter the drift region. In preferred embodiments, therefore, a desired mode of operation is selected by setting the ratio of the initial energy at which the ions enter the ion packet generator to the orthogonal energy imparted to the ions by the ion packet generator to the value which results in the desired value of n.
Although the mass of the ion appears in equation (1), it cancels from the expression for the ratio, so that the angle of entry into the drift region is independent of the mass of the ion.
In still further preferred embodiments, the energy of the ions entering the ion packet generator is controlled by accelerating the ions through a potential gradient as they approach the ion packet generator so that they enter it with an energy equal to the sum of their starting energy and the energy they acquire on travelling through the gradient. For the best results, therefore, the starting energy of each of the ions entering the ion packet generator must be similar. This is most conveniently achieved by use of an ion energy-collimating device upstream of the ion packet generator. Such devices include (without limitation thereto) a collisional-focusing gas cell and an electrostatic energy filter. A collisional-focusing gas cell causes the ions passing through it to repeatedly collide with molecules of an inert gas in the cell so that they emerge with a kinetic energy approximately equal to that of the thermal energy of the neutral gas molecules, irrespective of their original kinetic energy. Such devices are well known in the art, and are described, for example, in U.S. Pat. No. 4,963,736. Typically they may comprise a multipole electrode set to which radio frequency potentials are applied to confine the ions to the vicinity of the cell axis, and into which an inert gas at a pressure of about 10xe2x88x922 torr is introduced. Such a cell produces a beam of ions which comprises ions having approximately the same kinetic energy (usually less than about 3eV) and which are all travelling in the same direction. A preferred embodiment of the invention may therefore comprise a mass spectrometer which has an ion source, a collisional-focusing gas cell for collimating the ions generated by the source, equalizing their kinetic energies and transmitting them to a time-of-flight mass analyzer of the type previously described. In yet another embodiment the invention may comprise a tandem mass spectrometer which has an ion source, a first mass filter for transmitting ions having mass-to-charge ratios in a predetermined range, a collisional-focusing gas cell for receiving ions transmitted by said first mass filter, fragmenting them by collisions with neutral molecules of gas, collimating said fragment ions, equalizing their kinetic energies and transmitting them to a time-of-flight mass analyzer of the type previously described. Typically, the first mass analyzer will comprise a linear quadrupole mass filter or a quadrupole ion trap. It is also within the scope of the invention to combine the gas cell with the first mass analyzer, particularly in the case of a quadrupole ion trap.
It will be appreciated that in all these practical embodiments of the invention, the mode of operation of the time-of-flight analyzer (ie, the value of n) can be changed merely by adjusting the value of the potential gradient through which the ions are accelerated as they approach the ion packet generator. This is much simpler way of changing the number of reflections in a multiple reflection time-of-flight analyzer than is taught by any of the prior art discussed above.
Viewed from another aspect the invention provides a method of determining the mass-to-charge ratio of ions travelling in a beam by measuring their time of flight through a drift region having an axis, an entrance and an exit, there being also provided a first ion reflector disposed at said exit and a second ion reflector disposed in juxtaposition to said first ion reflector to reflect those packets of ions which enter it back through at least a portion of said drift region; said method comprising sequentially executing the following steps:
1) intermittently applying an electrostatic field to ions in said beam to inject packets of ions into said drift region at said entrance in an initial direction inclined to their original direction of travel in said beam;
2) when they reach said exit, reflecting ions comprised in said packets back into the said drift region towards said entrance by means of a first ion reflector;
3) by means of said second ion reflector, reflecting back towards said first ion reflector those of said packets of ions which enter said second ion reflector so that those packets of ions may be reflected to and fro between said first ion reflector and said second ion reflector and undergo an number n of reflections at said second ion reflector;
4) by means of an ion detector, detecting at least some packets of ions which have been reflected by said first ion reflector but which do not enter said second ion reflector; said method characterized in that the number n of reflections undergone by a said packet of ions at said second ion reflector before it is detected is determined by adjusting the inclination of said initial direction to said axis.
In preferred methods the number n of reflections at the second ion reflector may typically be chosen from the values n=0 through to n=2, but higher values may also be used. The significance of the different values of n has already been described. Thus in preferred methods, the mass-to-charge ratios of the ions to be analysed may be determined at high sensitivity and relatively low resolution by using a low value of n (preferably n=0, which corresponds to the conventional reflectron mode of operation of the analyzer), or alternatively with higher mass resolution with lower sensitivity using a value of n=1 or n=2.
The invention provides a simple and convenient method of changing between these modes, merely by adjusting the angle of inclination between the initial direction at which the ions enter the drift region and the axis of the drift region. As explained, the initial direction in which the ions are injected into the drift region, and therefore the value of n, is dependent on the ratio of the energy imparted by the electrostatic field to the ions in the beam to inject packets of ions into the drift region and the original energy they possessed while travelling in the beam. In preferred methods according to the invention, therefore, a desired mode of operation is selected by setting the ratio of the initial energy of the ions in the beam from which the ion packets are ejected to the energy imparted to them by the electrostatic field to the value which results in the desired value of n. Preferably, the electrostatic field is arranged to eject the ion packets from the beam in a substantially orthogonal direction.
In still further preferred methods, the energy of ions in the beam is controlled by accelerating them through a potential gradient before the electrostatic field is applied to eject packets of ions into the drift region. The desired value of n may then be selected simply by adjusting the potential difference through which the ions are accelerated. Preferably, in methods according to the invention, the ions are passed through an ion energy-collimating device before they are accelerated by the potential gradient. Such devices include (without limitation thereto) a collisional-focusing gas cell and an electrostatic energy filter. This ensures that the ions have substantially the same energy at the moment that they are injected into the drift region, so that the initial direction in the drift region is the same for all ions in any given packet of ions.
The invention further provides a method of mass spectrometry comprising generating a beam of ions whose mass-to-charge ratios are to be determined, passing said beam through a collisional-focusing gas cell in order to collimate the ions and to equalize their translational energies, and determining their mass-to-charge ratios by measuring their time of flight through a drift region in the manner described above. The invention further provides a method of tandem mass spectrometry comprising generating a beam of ions, passing said ions through a first mass filter to transmit only those ions having mass-to-charge ratios in a predetermined range, fragmenting at least some of those ions by collisions with molecules of inert gas, collimating the fragment ions and equalizing their translational energies, and determining the mass-to-charge ratios of the fragment ions by measuring their time of flight through a drift region in the manner described above.