Patent Description:
A TOF mass spectrometer can be employed to determine the mass-to-charge ratio of ions based on the time required for the ions to travel through a field free region to reach a detector. In practice, the resolution of a TOF spectrometer can be limited by a variety of factors, such as the initial positional distribution of ions along the TOF axis, the kinetic energy spread of ions as they enter the TOF spectrometer, and the length of field free region, among others. Although a number of advances have been made in improving the resolution of TOF spectrometers, there is still a need for further improvements.

<CIT> discloses a TOF mass spectrometer having an even number of ion mirrors in close proximity to a MALDI ion source and a field-free drift space between the exit from the mirrors and an ion detector.

According to the present invention, there is disclosed a time of flight mass spectrometer, comprising: an input orifice for receiving ions, a first ion acceleration stage for accelerating the ions along a first path, said first acceleration stage comprising first and second electrodes separated by a selected distance, wherein application of a voltage differential between said first and second electrodes generates an electrical field for accelerating the ions, a first ion reflector for receiving said accelerated ions and redirecting said ions along a second path different than the first path, a second ion reflector configured to redirect the ions propagating along the second path onto a third path, a detector for detecting at least a portion of the ions redirected by said second ion reflector, at least first and second field free drift regions disposed between said first acceleration stage and said detector, wherein said second field free region is disposed in proximity of the detector, and a second acceleration stage disposed between said first and second field free drift regions, a third electrode disposed at a distance relative to said second electrode, said second and third electrodes being held at a common voltage to generate said first field free drift region there between, a first grid disposed between said third electrode and said first ion reflector, said third electrode and said grid being held at a voltage differential to provide said second acceleration stage for ions traveling along said first path, wherein said first grid and said first ion reflector are held at a voltage differential configured to decelerate the ions as they propagate from said first grid to said first ion reflector, and wherein the lengths of the two field free drift regions are selected to provide at least first and second order correction of ion flight time to provide position focusing of the ions. The at least one ion reflector is also referred to as an "ion mirror" or a "reflectron".

In some embodiments, the second field free drift region has a length that is greater than that of the first field free region. The second electrode would be a grid in order to allow the ions to pass through. In some embodiments, a third electrode, also a grid, can be disposed at a distance relative to the second electrode, where the second and third electrodes are held at a common voltage to generate said first field free drift region there between.

In some embodiments, a third grid can be disposed between the third electrode/second grid and the first ion reflector, where the third electrode/second grid and the third grid are held at a voltage differential to provide a second acceleration stage for ions traveling along the first path. Further, the third grid which is also the entrance grid to the first ion reflector can be held at a voltage differential configured to decelerate the ions as they propagate into ion reflector from the third grid and to accelerate in the reverse direction as they propagate through the first ion reflector back to the third grid along the second path.

In some embodiments, the third grid can be configured such that the ions intersect the grid as they propagate along the second path from the first ion reflector to the second ion reflector. In this case, the same grid is also the entrance grid to the second reflector.

In some embodiments, the third grid and the second ion reflector are held at a voltage differential configured to cause the ions to decelerate as they propagate along the second path from the grid into the second ion reflector, where the second ion reflector is configured to redirect the ions along the third path back toward the grid. The voltage differential between the second ion reflector and the grid can cause the ions to accelerate as they move from the second ion reflector to the grid along the third path.

In some embodiments, the second field free drift region can extend from the grid to the detector.

In some embodiments, the length of the first field free drift region (d2) is provided by the Equation (<NUM>) presented further below, and the length of the second field free drift region (d6) is provided by Equation (<NUM>) presented further below.

In some embodiments, a second grid is disposed between the first grid and the first ion reflector at a distance (dff) from the first grid, wherein the first and the second grids are held at a common voltage to generate a third field free drift region therebetween. In some such embodiments, the length of the first field free drift region (d2) is provided by Equation(<NUM>) below, the length of the second field free drift region (d6) is provided by Equation (<NUM>) below based on a choice for the length of the third field free drift region (dff).

According to further aspects of the applicant's teachings, a time-of-flight mass spectrometer is disclosed, which can comprise a first ion acceleration stage for accelerating ions received through an input aperture (orifice), a first field free drift region for receiving the accelerated ions from the first acceleration stage, a second ion acceleration stage for accelerating ions exiting said first field free drift region, a second field free drift region for receiving the accelerated ions from the second acceleration stage, and a detector for receiving ions after their passage through the second field free drift region, wherein the field free drift regions are configured to ensure that the first and second derivatives of time-of- flight of ions through the spectrometer relative to a starting position of the ions vanish.

In some embodiments of the above time-of-flight mass spectrometer, the input aperture can be configured to receive ions in a direction orthogonal to a longitudinal axis of the spectrometer. Further, in some embodiments, a first electrode can be disposed in proximity of the aperture and can be configured to apply a voltage (e.g., a voltage pulse) to the entering ions to cause their deflection onto the longitudinal axis. In some embodiments, a second electrode can be disposed at a distance (d1) relative to the first electrode, where a voltage differential between the first and second electrodes provides the first ion acceleration stage. The second electrode would be a grid to allow the ions to pass through. In some embodiments, a third electrode, which can also be a grid, is disposed at a distance (d2) relative to the second electrode/grid, wherein the second and third electrodes/grids are held at a common voltage to generate said first field free drift region in a space therebetween. In some embodiments, a fourth electrode (which can also be a grid) can be disposed at a distance (d3) relative to the third electrode, wherein a voltage differential between the third and fourth electrodes (grids) generates said second ion acceleration stage. In some embodiments, the second field free drift region has a length (d4) and extends from the third electrode to the detector. In some embodiments, the length (d2) of the first field free drift region is provided by Equation (<NUM>) below, and the length (d4) of the second field free drift region is provided by Equation (<NUM>) below.

According to the present invention, there is also disclosed a method of performing time-of-flight mass spectrometry, comprising providing two or more ion acceleration stages between an ion entrance aperture and an ion detector, a first of the two or more ion acceleration stages comprising first and second electrodes separated by a selected distance, wherein application of a voltage differential between said first and second electrodes generates an electric field for accumulating the ions, providing two or more field free drift regions between said entrance aperture and the detector, wherein at least one of said field free drift regions is disposed between one of the two or more ion acceleration stages and the detector, the first of the two or more field free drift regions comprising a third electrode disposed at a distance from the second electrode, the second and third electrodes being held at a common voltage to generate the first of the two or more field free drift regions, providing two ion reflectors, wherein the second of the two or more ion acceleration stages is positioned between the first of the two or more field free drift regions and the first of the two ion reflectors, providing a grid disposed between said third electrode and the first of said two ion reflectors, said third electrode and said grid being held at a voltage differential to provide said second acceleration stage, wherein said first grid and said first ion reflector are held at a voltage differential configured to decelerate the ions as they propagate from said first grid to said first ion reflector, selecting lengths of said field free drift regions such that first and second derivatives of time-of-flight of the ions traveling from an initial ion position to said detector relative to the initial position vanish; wherein the length (d2) of the first of the two or more field free drift regions is calculated according to the equation: <MAT> and the length (d6) of the second of the two or more field free drift regions is calculated according to the equation <MAT> and the lengths of the two field free drift regions provide at least first and second order correction of ion flight time to provide position focusing of the ions.

In further aspects, a time-of-flight (TOF) mass spectrometer is disclosed, which can comprise an aperture for receiving a plurality of ions, at least one ion acceleration stage for accelerating the received ions along a first path, and two or more field free drift regions configured to provide spatial focusing of the accelerated ions at a selected location. The mass spectrometer can further comprise at least one ion reflector for receiving the ions from the spatial focusing location and for redirecting the ions along a second path different than the first path. The ion reflector can be configured to reduce the kinetic energy spread of the ions.

In some embodiments, the ion reflector can be configured to provide second order correction of the variation in the kinetic energy of the ions at said spatial focusing location. In some embodiments, the ion reflector can comprise a multi-stage, e.g., a two-stage, ion reflector.

In some embodiments, the lengths of two field free drift regions (d2 and d4) utilized to correct for variation in the initial ion position can be obtained by employing Equations (<NUM>) and (<NUM>) provided below. In some such embodiments, a two-stage ion reflector can be employed for correcting variation in the kinetic energy of the ions, where the parameters of the ion reflector can be selected by employing Equations (<NUM>) and (<NUM>) provided below.

The skilled person in the art will understand that the drawings, described below, are for illustration purposes only. The drawings are not intended to limit the scope of the applicant's teachings in any way.

In some embodiments, time-of-flight ("TOF") mass spectrometry analyzers are disclosed that can employ two or more field free drift regions to provide at least first and second order corrections of ion flight time with respect to a variation in ion initial position. In some embodiments, the lengths of the field free drift regions can be calculated based on the mathematical relations provided below. Further, in some embodiments, a TOF mass spectrometer is disclosed that employs two or more field free drift regions for providing positional focusing of ions at a selected distance from an ion reflector, where the ion reflector can be employed to reduce the effect on the flight time distribution caused by the kinetic energy spread of the ions before they reach a detector. Various terms and phrases employed herein to describe exemplary embodiments according to the applicants' teachings are used consistent with their ordinary meanings in the art. In particular, the term "field free drift region" as used herein refers to a region in which the electric field component along the direction of motion of ions has a magnitude below a given threshold of <NUM> V/m, and in many embodiments, the electric field component in a field free drift region along the direction of motion of the ions vanishes. Furthermore, the terms "ion reflector", "ion mirror" and "reflectron" are used interchangeably according to their common meaning in the art to refer to a device configured to reverse the direction of travel of an ion in a mass spectrometer.

<FIG> schematically depicts an embodiment of a time of flight (TOF) mass spectrometer <NUM> according to the applicant's teachings that includes an orifice (aperture) <NUM> for receiving ions from an upstream unit <NUM>. In some cases, the TOF spectrometer <NUM> can receive ions directly from an ion source, e.g., an electrospray ionization ("ESI") source, a desorption electrospray ionization ("DESI") source, or a sonic spray ionization ("SSI") source, among others. In other cases, the TOF spectrometer <NUM> can receive ions that have undergone various stages of filtering, fragmentation, and/or trapping. By way of example, in some implementations, the upstream unit can comprise an ion source <NUM>. Ions generated by the ion source <NUM> can enter the TOF spectrometer <NUM> for mass analysis.

Referring again to <FIG>, the ions enter the mass spectrometer along a direction <NUM>, which as discussed below, can be substantially orthogonal to an axial direction (herein also referred to as the "longitudinal direction") of the spectrometer (herein denoted as the AD direction). In particular, the mass spectrometer <NUM> can comprise an electrode <NUM>, e.g., in the form of a plate, to which a voltage (e.g., a pulse voltage) can be applied to cause a <NUM> degree change in the propagation direction of the ions entering the spectrometer. The spectrometer can comprise two additional electrodes <NUM> and <NUM>, which are separated from one another by a distance d2 and are held at a common DC voltage V2. The electrodes <NUM> and112 can be implemented in a variety of ways. For example, they can be in the form of plates having central openings through which ions can pass. In the following description, the location of an ion in the spectrometer relative to a reference point (e.g., the electrode <NUM>) is denoted by x.

The pair of electrodes <NUM> and <NUM> provides a first ion acceleration stage Z1 for the ions. In particular, a voltage differential (V2 - V1) between the electrodes <NUM> and <NUM> causes acceleration of the ions toward the electrode <NUM> and into a space between the electrodes <NUM> and <NUM>. Electrodes <NUM> and <NUM> would be grids or would have slits in order to allow the ions to pass through. As the electrodes <NUM> and <NUM> are held at a common voltage, the space between these two electrodes is a field free drift region Z2. In other words, there is no axial electric field in the region between the electrodes <NUM> and <NUM>, thus allowing the ions to drift in this region without being subjected to accelerating or decelerating forces. It should be understood that in the vicinity of the openings of the electrodes <NUM> and <NUM>, there can be fringing field that would have axial components. However, in many embodiments, the spacing d2 between the electrodes <NUM> and <NUM> can be much greater than the openings in the electrodes such that any fringing fields, if present, would have negligible effect in the propagation of the ions within this first field free drift region. As discussed in more detail below, this field free drift region is the first of two field free drift regions that are provided in this exemplary TOF spectrometer <NUM>.

With continued reference to <FIG>, a grid <NUM> can be disposed between the electrode <NUM> and an ion mirror <NUM>. In this embodiment, the grid <NUM> can be held at a DC voltage V3 different than V2 so as to accelerate the ions that leave the field free drift region Z2, e.g., via an opening in the electrode <NUM>. In other words, the voltage differential between the grid <NUM> and the electrode <NUM> provides a second ion acceleration stage. On the other hand, as the ions pass through the grid <NUM>, a decelerating electric field present between the ion mirror <NUM> and the grid cause the ions to decelerate, come to a stop, and be reflected by the ion mirror <NUM> back toward the grid <NUM>.

The ion mirror <NUM> can be implemented in a variety of ways. In this exemplary embodiment, the ion mirror <NUM> can be implemented as a single stage ion mirror that can be held at a voltage (e.g., DC voltage) V4. The mirror <NUM> causes the ions to change their propagation path from their initial path <NUM> to a different path <NUM>.

In this illustrative embodiment, the grid <NUM> can be configured to intersect the ions not only as they leave the field free drift region Z2 propagating along the path <NUM> but also as they propagate along the path <NUM> subsequent to their reflection by the ion mirror <NUM>. More specifically, the ions are accelerated subsequent to their reflection by the ion mirror <NUM> toward the grid <NUM>. In other words, the electric field established between the grid <NUM> and the ion mirror <NUM> causes deceleration of the ions as they move toward the ion mirror <NUM>, but cause acceleration of the ions as they move away from the ion mirror <NUM> toward the grid <NUM>.

In this illustrative embodiment, the spectrometer <NUM> can further comprise another ion mirror <NUM> that receives ions that are reflected by the first ion mirror after their passage through the grid <NUM> as they propagate along the path <NUM>. In this embodiment, similar to the first ion mirror <NUM>, the second ion mirror <NUM> can be a single stage ion mirror. The second ion mirror <NUM> can be held at a voltage V5, which can be the same or different from the voltage V4 at which the first ion mirror <NUM> can be held. The voltage differential between the second ion mirror <NUM> and the grid <NUM> causes deceleration of the ions as they move along the path <NUM> from the grid <NUM> to the second ion mirror <NUM>. The second ion mirror <NUM> reflects these ions onto a third path <NUM>. As the reflected ions move along the path <NUM>, the electric field between the grid <NUM> and the second mirror <NUM> causes their acceleration. Upon passing through the grid <NUM>, the ions reflected by the second ion mirror <NUM> enter a second field free drift region Z6 having a length d6. A detector <NUM> can be disposed at the end of the second field free drift region Z6 to detect the ions.

The lengths of the two field free drift regions (d2, d6) can be determined, as discussed below, to provide <NUM>st and <NUM>nd order corrections of ion flight time with respect to the initial ion position. In other words, the two field free regions can be configured to provide position focusing of the ions. In some embodiments, the following mathematical relations are employed to derive values for the lengths d2 and d6:.

In the equations outlined in this specification, the use of the ellipsis (. ) indicates that the equation is continued on the following line. The use of the ellipsis is not an indication that a portion of the equation has been intentionally omitted. In addition, in some instances, lines of equations which have been indented are continuations of the immediately preceding line. <MAT> <MAT> <MAT> <MAT> <MAT> wherein in the above Eq. (<NUM>) and Eq. (<NUM>):.

In various embodiments, the two ion mirrors are identical, as reflected in the above equations. In alternative embodiments, the two ion mirrors can be different. In other words, the dimensions and the fields generated by the two ion mirrors can be different. In some embodiments, such differences can be employed to provide higher order corrections or additional energy corrections.

To illustrate the use of the above mathematical relations in providing <NUM>st and <NUM>nd order corrections, <FIG> shows calculated time-of-flight (TOF) as a function of the ion initial position (which was selected to range from <NUM> to <NUM> relative the electrode <NUM>) for an <NUM> amu ion in the above TOF <NUM> with d2 = <NUM> and d6 = <NUM>, the ion mirror lengths were chosen to be <NUM> and the total ion flight distance was <NUM>. <FIG> and <FIG> show, respectively, the first derivative of TOF relative to the ion position along the ion path (dTOF/dx), as well as the second derivative of TOF relative to the ion position along the ion path (d<NUM>TOF/dx<NUM>). The beam width was assumed to be <NUM> (w = <NUM>). The values of the other parameters are shown in <FIG>, and include d1=<NUM>, d3=<NUM>, d4=<NUM>, d5=<NUM>, V1=<NUM> V, V3=-<NUM> V, V4=<NUM> V, V5=<NUM> V, E1=<NUM> V/mm, E3=<NUM> V/mm, E4=-<NUM> V/mm, E5=-<NUM> V/mm, res=<NUM>, delta t=<NUM> ps, L(Overall Distance)=<NUM>.

<FIG> show that the ion flight time traces a quartic function as the value of x ranges over the beam width (<NUM> in this example). This shows that not only a first order and a second order, but also a third order correction, were achieved, though d2 and d6 were not explicitly selected to provide <NUM>rd order correction. In many cases, a <NUM>rd order correction is not necessary given the limitations of the detector, HV (high voltage) stability, and signal acquisition technology. However, if needed, the <NUM>rd order correction can be taken into account in the context of the above mathematical formalism.

As shown in <FIG> and <FIG>, the <NUM>st and <NUM>nd order corrections provide a wide and flat region for the initial ion locations (e.g., in this case between <NUM> and <NUM> relative to the electrode <NUM>) in which the first and second derivatives of TOF relative to ion position vanish. Given the idealized conditions of no variation anywhere except ion position and no initial kinetic energy along the TOF longitudinal axis, this TOF can theoretically focus an <NUM> wide ion beam into a <NUM> ps wide ion flight time distribution (all inclusive, not FWHM), thereby providing a resolution of <NUM> million (mass/Δmass, Δmass=max-min, not FWHM).

<FIG> shows simulated ion trajectory in this illustrative TOF spectrometer in the ion acceleration and ion mirror sections and <FIG> shows ion trajectories to the focus point (the long field free trajectory was at an angle of <NUM> degrees relative to the longitudinal axis of the spectrometer). <FIG> shows simulated potential energy of the ions along their trajectories as they pass through the TOF <NUM>. The simulations were done with ion orthogonal kinetic energy of <NUM> eV as the ions enter the spectrometer. Although the initial positions of the ions along the TOF axis was simulated to be at different locations, the ions were tightly focused at the detector.

<FIG> schematically depicts a TOF spectrometer <NUM> according to another embodiment of the invention that varies from the embodiment of <FIG> in that it includes an additional field free region. More specifically, in various embodiments, two grids <NUM> and <NUM> are disposed between the two ion mirrors <NUM> and <NUM>. The grids <NUM> and <NUM> are held at a common voltage V3 so as to generate a field free drift region Zff between the grids. Similar to the previous embodiment, a voltage V1 (e.g., a pulse voltage) applied to the electrode <NUM> causes the ions entering the spectrometer to be redirected toward the first field free drift region Z2 while being accelerated by the voltage differential (V2-V1) applied between the electrodes <NUM> and <NUM>. After leaving the field free region Z2, the ions are accelerated toward the grid <NUM> via the voltage differential (V3-V2) applied between the grid <NUM> and the electrode <NUM>. The ions then pass through the second field free drift region Zff and continue to propagate toward the ion mirror <NUM>. The voltage differential between the ion mirror <NUM> and the grid <NUM> (V4-V3) decelerates the ions as they propagate toward the ion mirror <NUM>, which causes the reflection of the ions back toward the grid <NUM>. The reflected ions are accelerated as they move from the ion mirror <NUM> to the grid <NUM>. The reflected ions pass through the field free drift region Zff established between the two grids <NUM> and <NUM> and propagate toward the second ion mirror <NUM>. The ions are decelerated as they move toward the second ion mirror <NUM> and are reflected by that ion mirror back toward the field free drift region Zff between the two grids <NUM> and <NUM>. After passage through the field free region Zff, they enter a long field free drift region Z6 having a length d6 that extends to a detector <NUM>. In various embodiments, as shown here, both ion mirrors can be single stage mirrors, though in other embodiments one or both of the ion mirrors can be multi-stage (e.g., two-stage) ion mirrors. In some implementations of this embodiment, the length of the final field free drift region (d6) can be shorter than the corresponding length of the respective field free drift region in the TOF <NUM> of other embodiments. By way of example, in some embodiments, for each mm length of the additional field free region Zff, the final field free region Z6 can be shortened by <NUM>.

The lengths of the field free regions Z2 and Z6 (d2 and d6) can be determined by employing the following mathematical relations in which dff is a parameter. By choosing a value of dff, the mathematical Equations (<NUM>) and (<NUM>) can be used to obtain values for the lengths d2 and d6. In some cases, an initial choice for dff may not yield reasonable values for d2 and d6 (e.g., they may not be positive values). In such cases, other values for dff can be iteratively selected until reasonable values for d2 and d6 are obtained. As in the previous embodiment, the first derivative of TOF with respect to ion position (x) can be employed to obtain a value of d6, and the second derivative of TOF with respect to ion position (x) can be employed to obtain a value for d2. The value of d2 can be independent of d6 and dff while the value of d6 depends on d2 and dff. <MAT> <MAT> <MAT> <MAT> <MAT> <MAT> <MAT> wherein in the above Equations <NUM>-<NUM>:.

<FIG> schematically depicts a TOF <NUM> according to yet another embodiment according to the applicants' teachings that, similar to the previous embodiment, includes two grids <NUM> and <NUM> between which a field free drift region Zff can be established. In addition, similar to the previous two embodiments, a field free drift region Z2 can be established between the two electrodes <NUM> and <NUM>. Unlike the previous two embodiments, the TOF <NUM> lacks a long field free region that would extend from one of the grids to the detector. Rather, in this embodiment, a detector <NUM> can be disposed such that the detector's impact surface shares a plane with the grid <NUM> (i.e., the detector's impact surface can be coplanar with the grid <NUM>). Hence, the ions reflected by the second ion mirror <NUM> encounter the detector <NUM> at the end of their passage through the field free drift region Zff between the grids <NUM> and <NUM>. The ions enter the TOF <NUM> through an aperture and are reflected by an electrode <NUM> held at voltage V1. In some embodiments, the lengths d3, d4 and d5 can be identical while in other embodiments at least two of those lengths can be different.

To obtain the values of d2 and dff for the above TOF <NUM>, d6 can be set to zero in the above Equation <NUM> presented in connection with the previous embodiment, and dff can be solved instead of d6.

In some implementations of the TOF <NUM>, the ion mirror lengths (i.e., d4 and d5) can be selected to be equal to the length of the second ion accelerator stage (i.e., d3).

The above mathematical relations were utilized to simulate the time-of-flight and trajectories of ions having an amu of <NUM> through a hypothetical implementation of the above TOF <NUM> having the following parameters: d1 = <NUM>, d2 = <NUM>, d3 = <NUM>, d4 = <NUM>, d5 = <NUM>, V1 = <NUM> volts (V), V2 = <NUM>, V3 = -<NUM> V, V4 = <NUM> V, V5 = <NUM> V, and dff = <NUM>, and the ion beam was assumed to be <NUM> wide. The ion flight path was <NUM>, long enough to realize high performance (<NUM> beam was focused to <NUM> ps, maximum resolution <NUM>,<NUM>), and the overall length of the analyzer was about <NUM>. Furthermore, E1=<NUM> V/mm, E3=<NUM> V/mm, E4=-<NUM> V/mm, and E5=-<NUM> V/mm.

<FIG> shows the ion TOF as a function of ion position along the TOF axis AD, <FIG> shows the first derivative of TOF relative to ion position along the TOF axis AD, and <FIG> shows the second derivative of TOF relative to ion position along the TOF axis AD. As shown in <FIG> and <FIG>, the <NUM>st and <NUM>nd order corrections provide a wide and flat region for the initial ion locations (e.g., in this case for ion positions between <NUM> and <NUM> relative to <NUM>) in which the first and second derivatives vanish.

<FIG> shows calculated trajectories of a plurality ions with <NUM> eV orthogonal energy as they enter the above simulated TOF spectrometer based on the TOF <NUM>, as well as a range of initial (starting) positions, according to some embodiments of the applicant's teachings. <FIG> shows calculated ion trajectories superimposed on a potential energy diagram. The ions come to a tight focus at the plane the impact surface of the detector shares with entrance grid to the first ion mirror.

Other embodiments of TOF spectrometer according to the applicant's teachings can include additional field free drift regions. Further, in some embodiments, one or more of the ion mirrors can be two-stage mirrors. Some of such embodiments can allow for providing higher order corrections and/or for combining spatial and energy focusing.

By way of example, <FIG> schematically depicts a TOF spectrometer <NUM> according to one such embodiment that is similar to the embodiment of <FIG> in that it comprises two field free regions Z2 and Z4 and a grid <NUM> disposed between two ion mirrors <NUM> and <NUM>. However, unlike the embodiment of <FIG> in which the ion mirrors are single-stage ion mirrors, in this embodiment, the ion mirrors are two-stage ion mirrors.

By way of another example, <FIG>. schematically depicts another TOF spectrometer <NUM> that is similar to the embodiment shown in <FIG> above having two grids <NUM> and <NUM> between which a field free drift region Zff can be established in addition to the field free drift regions Z2 and Z6. However, unlike the above embodiment of <FIG> in which the ion mirrors are single-stage ion mirrors, the TOF <NUM> includes two ion mirrors <NUM> and <NUM>, both of which are two-stage ion mirrors.

<FIG> schematically depicts a TOF spectrometer <NUM> according to another embodiment that includes two two-stage ion mirrors <NUM> and <NUM> and four field free drift regions Z2, Zff, Zm1 and Zm2. Each of the two additional field free drift regions Zm1 and Zm2 can be disposed between one of the two-stage ion mirrors and one of the grids <NUM> and <NUM> between which the field free drift region Zm1 and Zm2 can be disposed.

The above mathematical formalism can be employed to analyze these additional embodiments, e.g., to determine the lengths of the field free drift regions.

The use of ion mirrors in various embodiments, such as those discussed above, to fold the path of the ion beam can allow for implementing the present teachings, including the use of multiple field free regions, in a compact configuration. For example, the use of ion mirrors can allow for utilizing multiple field free regions while maintaining the physical dimensions of the spectrometer within a desired range.

Applicant's teachings are, however, not restricted to the above embodiments but can be applied to any TOF geometry. By way of example, <FIG> schematically depicts a linear TOF analyzer <NUM> according to another embodiment that can comprise an entrance aperture <NUM> through which ions enter the analyzer orthogonal to analyzer's axis (AD). A pulsed voltage applied to an electrode <NUM> causes a <NUM>-degree deflection of the ions to cause the ions to propagate along the analyzer's axis AD. A voltage differential applied between an electrode <NUM> and the electrode <NUM> causes acceleration of the ions (first ion acceleration stage Z1). The accelerated ions then enter a first field free drift region Z2 established between the electrode <NUM> and another electrode <NUM>, which are held at a common voltage. After passage through the first field free drift region Z2, the ions are subjected to a second ion acceleration stage Z3, which can be generated by a voltage differential applied between the electrode <NUM> and an electrode <NUM>. The ions then enter a second field free region Z4, which can be much longer than the first field free drift region Z2 and extends to a detector <NUM>.

Unlike the previous embodiments, the TOF spectrometer <NUM> does not include any ion mirrors to cause folding of the ion trajectories as they travel from the analyzer's entrance to the detector.

The lengths of the two field free regions (i.e., d2 and d4) can be determined, as discussed below, to provide <NUM>st and <NUM>nd order corrections of ion flight time with respect to the initial ion position. In other words, the two field free regions can be configured to provide position focusing of the ions. In this embodiment, the following mathematical relations are employed to derive values for the lengths d2 and d4: <MAT> wherein: <MAT> And <MAT> <MAT> <MAT> <MAT> <MAT>.

<FIG> depicts a calculated TOF for ions traveling through a theoretical implementation of the above linear TOF analyzer for which the first and second order corrections of TOF relative to ion position along the TOF <NUM> was provided by using the above Equations <NUM>-<NUM>. The parameter of this TOF were as follows: d1=<NUM>, d2=<NUM>, d3=<NUM>, d4=<NUM>, V1=1500V, V2=0V, V3=-6000V.

In some embodiments, two or more field free regions can be employed to provide first and second order corrections for the TOF of ions with respect to a spread in initial ion positions, and one or more ion mirrors can be employed to provide first (and in some cases second order) corrections with respect to a spread in the kinetic energy of the ions. For example, one or more ion acceleration stages together with one or more field free drift regions can be employed to temporally focus ions (bunch up the ions spatially), via correcting for ion position or velocity correlated ion position, at a virtual focus location at the entrance of an ion mirror, and the ion mirror can then be configured to achieve a second order correction of ion flight time relative to variation in ion kinetic energy.

By way of example, <FIG> schematically depicts a TOF spectrometer <NUM> according to such an embodiment in which first and second order corrections of TOF for both ion position and ion energy are provided, but at different locations in the spectrometer. The position correction can be for initial ion position, and the energy correction can be for ion energy variation at the temporal focus of the ion position, which in this embodiment can be at the entrance to the ion mirror. The TOF spectrometer <NUM> includes an entrance aperture <NUM> through which ions can enter the spectrometer along a direction orthogonal to TOF axis (a direction parallel to the velocity vectors of the ions) of the spectrometer. A deflection electrode <NUM> to which a voltage, e.g., a pulsed voltage, can be applied causes the deflection of entering ions onto the TOF axis. A voltage differential applied between the deflection electrode <NUM> and another electrode <NUM> provides a first acceleration stage Z1. Another electrode <NUM> disposed at a distance d2 relative to the electrode <NUM> can be held at a common voltage with electrode <NUM> such that the space between the two electrodes is a first field free drift region d2. A second ion acceleration stage Z3 can be provided by a voltage differential applied between the electrode <NUM> and another electrode <NUM> disposed at a distance d3 relative to the electrode <NUM>. The spectrometer <NUM> includes another electrode <NUM> disposed at a distance d4+d5 relative to the electrode <NUM> and can be held at a common voltage with that electrode, thereby generating a second field free drift region Z4+Z5.

As discussed further below, the lengths d3 and (d4+d5) of the field free drift regions can be configured based on other parameters, e.g., the electric fields within the acceleration regions, to obtain first and second corrections of the TOF relative to initial ion position, thereby temporally focusing the ions in the middle of the second field free drift region Z4+Z5.

Upon exiting the second field free drift region Z4+Z5, the ions enter a two-stage ion mirror <NUM>. The two-stage ion mirror <NUM> can include an electrode 1616A disposed at a distance d6 from the electrode <NUM> and another electrode 1616B disposed at a distance d7 from the electrode 1616A. A voltage differential between the electrodes <NUM> and 1616A provides a first deceleration of the ions, and a voltage differential between 1616A and 1616B provides a second deceleration of the ions such that the ions come to a stop and reverse direction. The reflected ions are then accelerated by traversing the regions between the electrodes 1616B and 1616A and the electrode 1616A and <NUM> to enter a field free drift region Z8 that extends to a detector <NUM>. The first focal point can be between the two grid elements <NUM> and <NUM>.

In some embodiments, the following mathematical relations can be employed to obtain various system parameters, such as the lengths of the field free regions and the ion energy spread at the virtual focus. The mathematical relations are designed to achieve <NUM>nd order correlation focusing from the first acceleration stage to a virtual focus location (labeled <NUM>st focus in <FIG>), and then to achieve <NUM>nd order energy focusing from the virtual focus location to the detector. To accomplish this, Newton's equations of motion are applied for ions as they propagate through regions (z1, z3, z6, and z7) in which the ions are subjected to linearly accelerating fields, and field free regions (d2, z4, z5 and z8).

The field strengths in the acceleration regions are determined as the electrostatic field between two parallel conductors held at a potential difference: <MAT> <MAT> <MAT> <MAT>.

The force on the ion in these (or any) electric field can be given by: <MAT>.

Thus, the ion undergoes an acceleration given by: <MAT> where the acceleration, a can be written as: <MAT>.

For correlation focusing, the following relation can be substituted for position, x: <MAT>.

The new term mc is the slope of the correlation. The unit of measure for mc is time. The following relations can then be obtained for flight times in various regions: <MAT> <MAT> <MAT> <MAT>.

Thus, the total time of flight from the initial ion position to the virtual focus is: <MAT>.

Substituting the values for t1, t2, t3 and t4, tof can be written as: <MAT>.

The first and second derivative of tof with respect to v1 can then be calculated and set to zero: <MAT> <MAT>.

By setting Equations <NUM> and <NUM> to zero, values of d2 and d4 can be determined as follows: <MAT> <MAT>.

In some embodiments, the various voltages and dimensions utilized as parameters in the above equations can set to reasonable values so long as the resultant values of d2 and d4 are real, positive and reasonable to obtain correction for velocity correlated ion position to the second order at the first virtual focus location. In other embodiments, the ion position, rather than velocity correlated ion position, can be employed in the above mathematical relations.

The remainder of the analyzer can be then utilized to correct for spread in ion energy to the second order Again, Newton's equation of motion are employed to determine the ion flight times in the remaining sections of the TOF analyzer. The equations for the second part of the analyzer can be constructed in energy terms and then differentiated with respect to energy, or can be constructed in terms of position and velocity and then differentiated with respect to position or velocity. Both types of equations are provided below: <MAT> <MAT> <MAT> <MAT> <MAT> <MAT> <MAT> <MAT> <MAT> <MAT> <MAT> <MAT>.

The above equations for the TOF through the <NUM>nd part of the analyzer can then be differentiated with respect to U5 (<NUM>st and <NUM>nd derivatives) and set to zero to obtain the following parameters: <MAT> <MAT> <MAT> <MAT> <MAT> <MAT> <MAT> <MAT>.

Since we actually do not set the field value, but a voltage, we can solve for the voltage: <MAT>.

By setting the parameters sum and mirror in accordance with the above equations, the ion energy spread at the virtual focus can be corrected to the second order.

The overall TOF equations can be given by the following relation: <MAT>.

<FIG> shows TOF as a function of ions velocity correlated initial position (the initial ion positioned can be referenced relative to the deflection electrode <NUM>), <FIG> shows the first derivative of TOF relative to the ion velocity correlated initial position and <FIG> shows the second derivative of TOF relative to the ion velocity correlated initial position for a theoretical implementation of the above TOF spectrometer with the following parameters with first and second order corrections of TOF relative to the initial ion position but without second order energy correction for an ion having a mass of <NUM> amu: d1 = <NUM>, d2 = <NUM>, d3 = <NUM>, d4 = <NUM>, d5 = <NUM>, d6 = <NUM>, d7 = <NUM>, d8 = <NUM>, V1 = <NUM> V, V2 = <NUM>, V3 = -<NUM> V, V4 = -<NUM> V, V5 = <NUM> V, length of ion flight = <NUM>, length of analyzer = <NUM>, beam waist = <NUM>, kinetic energy of incoming ions:<NUM> eV.

<FIG>, <FIG>, and <FIG> show respective TOF as a function of ion kinetic energy from the virtual focus location to the detector, first derivative of TOF relative to the ion kinetic energy at the virtual focus location, and second derivative of TOF relative to the ion kinetic energy at the virtual focus location with second order correction of TOF relative to variation in kinetic energy given the range of the kinetic energy spread at the virtual focus location as a consequence of the previous second order correction of TOF with respect to variation in initial velocity correlated ion position for a theoretical implementation of the above TOF spectrometer with the following parameters for an ion having a mass of <NUM> amu: d1 = <NUM>, d2 = <NUM>, d3 = <NUM>, d4 = <NUM>, d5 = <NUM>, d6 = <NUM>, d7 = <NUM>, d8 = <NUM>, V1 = <NUM> V, V2 = <NUM>, V3 = -<NUM> V, V4 = -<NUM> V, V5 = <NUM> V, length of ion flight = <NUM>, length of analyzer = <NUM>, beam waist = <NUM>, kinetic energy of incoming ions:<NUM> eV. And <FIG> shows the comprehensive TOF given a range of velocity correlated ion positions when both second order corrections for velocity correlated position and energy are implemented, indicating an enhanced performance. This analyzer can focus an velocity correlated beam that has a range of velocity of ±<NUM>/s to 35picoseconds at the detector (<NUM>,<NUM> theoretical resolution limit). Such a beam will have a dimension of about <NUM>.

<FIG> shows an exemplary mass spectrum recorded using a TOF analyzer of protonated ALILTLVS peptide having a mass of <NUM> using an embodiment described by <FIG> and Equation <NUM>.

<FIG> shows an exemplary mass spectrum recorded using a TOF analyzer of protonated reserpine having a mass of <NUM> using an embodiment described by <FIG>.

Claim 1:
A time of flight mass spectrometer (<NUM>, <NUM>), comprising:
an input orifice (<NUM>) for receiving ions,
a first ion acceleration stage (Z1) for accelerating the ions along a first path (<NUM>), said first acceleration stage (Z1) comprising first and second electrodes (<NUM>, <NUM>) separated by a selected distance (d1), wherein application of a voltage differential between said first and second electrodes (<NUM>, <NUM>) generates an electrical field (E1) for accelerating the ions,
a first ion reflector (<NUM>) for receiving said accelerated ions and redirecting said ions along a second path (<NUM>) different than the first path (<NUM>),
a second ion reflector (<NUM>) configured to redirect the ions propagating along the second path (<NUM>) onto a third path (<NUM>),
a detector (<NUM>) for detecting at least a portion of the ions redirected by said second ion reflector (<NUM>),
at least first and second field free drift regions (Z2, Z6) disposed between said first acceleration (Z1) stage and said detector (<NUM>), wherein said second field free region (Z6) is disposed in proximity of the detector (<NUM>), and
a second acceleration stage (Z3) disposed between said first and second field free drift regions (Z2, Z6),
a third electrode (<NUM>) disposed at a distance relative to said second electrode (<NUM>), said second and third electrodes being held at a common voltage to generate said first field free drift region (Z2) there between,
a first grid (<NUM>) disposed between said third electrode (<NUM>) and said first ion reflector (<NUM>), said third electrode (<NUM>) and said grid (<NUM>) being held at a voltage differential to provide said second acceleration stage (Z3) for ions traveling along said first path (<NUM>),
wherein said first grid (<NUM>) and said first ion reflector (<NUM>) are held at a voltage differential configured to decelerate the ions as they propagate from said first grid (<NUM>) to said first ion reflector (<NUM>), and
wherein the lengths of the two field free drift regions are selected to provide at least first and second order correction of ion flight time to provide position focusing of the ions.