WO2004021386A2 - Mass spectrometer - Google Patents

Abstract

A method is described for space-focusing ions accelerated to constant momentum that includes accelerating ions in an electric field having a negative gradient in the direction the ions are accelerated. A single stage ion accelerator (400, 410) that provides a decreasing electric field along the ion optical axis also is disclosed. Combined with a detector (414, 418) placed onto a space-focal plane where ions are focused after being accelerated, the accelerator provides a simple, sensitive time-of-flight mass spectrometer (416). In combination with an energy analyzer (410), the disclosed decreasing electric field ion accelerator provides a mass analyzer (416) that can measure constant momentum spectra, and that may be combined with existing mass spectrometers to enable a number of novel mass spectrometric methods.

Description

MASS SPECTROMETER

Related Applications

This claims the benefit of U.S. Provisional Application No. 60/407,430 filed August 30, 2002.

Field

The invention concerns mass spectrometers. More specifically, the invention relates to time-of-flight (TOF) mass spectrometers that may be operated in both constant energy and constant momentum modes, and methods for obtaining mass spectra in a constant momentum mode.

Background

Mass spectromefry includes a broad range of instruments and methodologies used to elucidate the structural and chemical properties of molecules, to identify the compounds present in physical and biological matter, and to quantify the chemical substances found in samples of such matter. At the most rudimentary level, a mass spectrometer comprises an ion source, a mass analyzer, and a detector. There are several types of ion sources, analyzers, and detectors, and these elements can be assembled in different combinations to form different types of mass spectrometers. Mass spectrometers can generate useful structural information from minute

1 quantities of pure substances (in typical cases, 1-20x10^" g, and in favorable cases, 1-50x10^"15 g) and, as a consequence, can identify compounds at very low concentrations (in favorable cases, one part in 10 ) in chemically complex mixtures. The power of this analytical science is evidenced by the fact that mass spectromefry has become a necessary adjunct to research in every division of natural and biological science and provides valuable information to a wide range of technologically based professions, such as medicine, law enforcement, process control engineering, chemical manufacturing, pharmacy, biotechnology, food processing and testing, and environmental engineering. In these applications, mass spectromefry is used to identify structures of biomolecules, such as carbohydrates, nucleic acids and steroids; sequence biopolymers, such as proteins and oligonucleotides; determine how drugs are used by the body; perform forensic analyses (e.g., confirm and quantitate drugs of abuse); analyze environmental pollutants; determine the age and origins of geochemical and archaeological specimens; identify and quantitate components of complex organic mixtures; and perform ultrasensitive multi-element analyses of inorganic materials, such as metal alloys and semiconductors.

A mass spectrometer typically measures the masses of individual molecules that have been converted to gas-phase ions, i.e. to electrically charged molecules in the gaseous state. Conversion to gas-phase ions is an essential prerequisite to the mass sorting and detection processes that occur in a mass spectrometer. The principal parts of any mass spectrometer are its ion source, mass analyzer, detector, and data handling system. Samples, which may be a solid, liquid, or vapor, are introduced into the ion source where ionization and volatilization occur. The phase and state of the sample and the size and structure of the molecules determine which physical and chemical processes to use in the ion source to convert the sample into gas-phase ions. Ionization requires that energy be transferred from an external agent into the sample molecules. In most instances, this causes some of the nascent molecular ions to explode (either somewhere in the ion source or just after they exit the ion source) into a variety of fragment ions. Both surviving molecular ions and fragment ions formed in the ion source are passed on to the mass analyzer, which uses electromagnetic forces to sort them according to their mass-to-charge (m/z) ratios or a related mechanical property, such as velocity, momentum, or energy. After being separated by the analyzer, the ions are successively directed to the detector by a scanning process. The detector generates electrical signals whose magnitudes are proportional to the number of ions striking the detector per unit time. The data system records these electrical signals and displays them on a monitor or prints them out in the form of a mass spectrum, i.e. a graph of signal intensity versus m/z. In principle, the pattern of signals registered in the mass spectrum of a pure compound constitutes a unique chemical fingerprint from which the compound's molecular mass and, sometimes, its structure can be deduced.

At present, the most widely used mass-selective devices are electric/magnetic sectors, quadrupole mass filters, quadrupole ion traps, Fourier transform ion cyclotron resonance (FT-ICR) cells, and TOF tubes. Mass spectrometers based on TOF analysis are currently playing a major role in the revolutionary expansion of mass spectrometric applications into molecular- biological research and biotechnology. TOF mass analyzers are fundamentally the simplest and the least expensive to manufacture. All TOF mass spectrometers in use today function in what is referred to as a constant energy mode. In this mode, a spatially restricted ensemble of ions in vacuum is subjected to a constant force over some fixed distance. This condition assures that essentially the same amount of work is performed, irrespective of individual mass, on all ions of like charge in the ensemble and that such ions thereby acquire, on the average, the same kinetic energy. Variations that occur about the average are the result of the ions in the volume sampled having had different initial velocities and different starting positions. For ions of like charge in an ensemble thus accelerated to constant energy, the time (t) required to traverse a specified distance in field free space is, to the first order, directly proportional to the square root of ionic mass (m), i.e. t ∞ m^y and accordingly, the mass resolving power (ml Am) is inversely proportional to twice the resolution in the measured time (Δt), i.e. ml Am = tl2Δt. In TOF mass spectromefry therefore, the m/z values of ions contained in an accelerated ensemble are determined simply by measuring the ions' successive transit times through a flight tube to a detector (typically > 10 μs).

The m/z range of a TOF mass spectrometer is theoretically unlimited. With the other four forms of commonly used mass analyzers, the settings of one or more parameters determine the m/z of the ions that are allowed to pass to the detector. In order for ions with a different m/z to be detected, these settings must be increased or decreased. Ultimately, some fundamental or practical characteristic of the mass analyzer, which limits the extent to which its /z-determining parameters can be changed, imposes an upper limit on the size of the ions that can be analyzed. In a TOF mass analyzer, increasingly larger ions simply take conespondingly longer times to reach the detector, and there is no fundamental limit to the length of time that can be measured. Because of this unique feature, TOF mass analyzers are especially useful for analyzing large biological molecules. In general, a TOF mass spectrometer does not acquire a mass spectrum by scanning. Scanning denotes a continuous increasing or decreasing of a mass analyzer's /z-determining parameters over a predetermined range so ions over a corresponding range of m/z values can be detected in succession. Scanning reduces the analytical efficiency of a mass spectrometric analysis because, while the ions of one particular m/z are being detected, the ions of all other m/z values released into the analyzer are being irretrievably lost in the instrument. By contrast, all of the ions released in a single burst into a TOF mass analyzer are detected and recorded without changing any instrumental parameters. Consequently, TOF mass spectrometers are particularly fast, sensitive instruments. Full mass spectra can be obtained, without losing spectral information or sensitivity, at a frequency of 5-10 kHz. This high spectral acquisition rate is particularly powerful when mass spectromefry is performed in conjunction with gas or liquid chromatography. The combination makes it possible to (1) monitor all information about any ion at any time in the elution profile of a the chromato graphic analysis; (2) improve the signal- to-noise ratio and, in turn, the sensitivity by intensive data averaging; and (3) accurately monitor fast separations that result in the production of extremely narrow chromatographic peaks.

Performing multiple stages of analysis in tandem can significantly enhance the utility of mass spectromefry. Tandem instruments exist in two general forms. A transmission tandem mass spectrometer comprises two or more mass-selective devices, which can be operated independently, arranged one after another with each mass analyzer separated from the preceding one by a region in which ion- dissociation can be induced. An ion-trapping tandem mass spectrometer comprises a single cell that functions (for one or more cycles) alternately as a mass-selective device and a region for inducing ion-dissociation. Independent operation of the mass analyzers in a tandem system makes it possible to perform analyses based on changes in mass, charge, or reactivity, and on the ability of one or more of the mass analyzers to register those changes. Tandem mass spectrometers can also be used to substantially improve signal-to-background ratios and, thus, sensitivity by eliminating interferences in certain types of analyses when the ion signal at the m/z of interest is produced by more than one compound. Increasingly, novel instruments are appearing that make it possible to use multiple stages of mass spectromefry (MSⁿ) to probe ion structure as well as to increase specificity in the identification of molecular components of complex mixtures.

The standard modes of tandem mass specfrometric analysis that have evolved over the past two decades are well described in text books [e.g., Mass Spectrometry Principles and Applications. By E. De Hoffmann, J. Charette, and N. Stroobant; John Wiley & Sons: New York, 1996, or Introduction to Mass Spectrometry, 3^rd Edition. By J.T. Watson; Lippincott-Raven Publishers: Philadelphia, 1997.] and in reference books [e.g., Methods in Enzymology, J. A. McCloskey, Ed. ; Academic Press, Inc. : San Diego, Vol. 193 , 1990] . The most frequently practiced form of tandem mass spectrometry is MS² or MS/MS. MS² analyses are performed in one of three scanning modes: product-ion scans, precursor-ion scans, and neutral-loss scans. In a product-ion scan, the first mass analyzer (MSI) is set to fransmit ions formed in the instrument's ion source at only one particular m/z value. The selected ions, which are called precursor ions, are passed into a region where they are induced to dissociate into fragments. The charged fragments, which are called product ions, resulting from these dissociations are passed into the second mass analyzer (MS2), which is programmed to scan over a range that covers the various m/z values of all the product ions. Only mass peaks corresponding to the charged fragments of the precursor ion selected by MS 1 appear in the resulting product-ion mass spectrum. If the sample is a pure compound and fragment-forming ionization has been used, individual fragment ions originating in the ion source can be selected as precursor ions; their product-ion spectra (which may be thought of as mass spectra within a mass spectrum) can provide much additional structural information about the analyte. If the sample is a mixture and nonfragment-forming ionization is used to produce predominantly molecular ions, the second stage of mass analysis can provide an identifying mass spectrum for each component in the mixture. In a precursor-ion scan, MSI is programmed to scan over a range that covers the various m/z values of all the ions formed in the instrument's ion source, while MS2 is set to transmit product ions at one particular m/z value. In this manner, only mass peaks corresponding to precursor ions that can fragment into a product ion with the specific m/z value transmitted by MS2 appear in the resulting precursor-ion mass spectrum. In a neutral-loss scan, MSI is programmed to scan over a range that covers the various m/z values of all the ions formed in the instrument's ion source while MS2 is programmed to simultaneously scan over a range that is incrementally offset from MSI 's mass-range by a constant mass-value. In this manner, only mass peaks conesponding to precursor ions that lose a neutral fragment (e.g. a water or carbon monoxide molecule) whose mass is equal to the constant mass-offset between the scanning ranges of MSI and MS2 appear in the resulting neutral-loss mass spectrum.

The means employed to induce fragmentation of precursor ions in MSⁿ experiments vary. The most widely used technique is known as collisionally induced (or activated) dissociation (CDD or CAD). CID (CAD) is a process whereby precursor ions are collided with neutral target atoms or molecules (typically noble gases, for example helium, argon, xenon, and mixtures thereof). As a result of the collisions, some of any given precursor ion's kinetic energy is converted into internal energy. If there is enough excess internal energy to break chemical bonds, the ion will dissociate into a set of two or more smaller fragment (product) species, at least one of which must be an ion. If a precursor ion is accelerated to a kinetic energy of approximately one kilovolt or higher prior to entering the CID cell (high energy CID), any resulting collision with a target atom will result in an electronic excitation of the precursor ion that dissipates relatively quickly into an almost uniform distribution of internally excited vibrational and rotational states. In this state of approximately uniform internal excitation, virtually all structurally possible fragmentations of the ion have some probability of occurring. If a precursor ion possess a kinetic energy in the range of 1 eV to several hundred eN (for example, 500 eV or less) prior to entering the CID cell (low energy CID), it may acquire sufficient vibrational excitation after a succession of collisions with target atoms to induce fragmentation. Vibrational excitation resulting from these successive low energy collisions in the gas phase typically results in a non-uniform internal energy distribution that favors fragmentation pathways in the precursor ion that generally are markedly different than those followed after a single high energy collision in the gas phase. In the low energy case, the fragmentation pattern depends strongly on the kinetic energy of the collisions. For example, the fragmentation pattern produced after precursor ions of a given structure are subjected to 20 eN collisions may be very different from the fragmentation pattern produced after precursors with identical structures are subjected to 50 eN collisions. A low energy fragmentation pattern will also depend strongly on the mass, pressure, and temperature of the target gas. For these reasons, low energy CID is less reproducible than high energy CID. CID cells, as well as their construction and operation, are known in the art. Low energy CID cells typically are more complex than high-energy CID cells due to the requirement that ions entering the dissociation cell may need to be decelerated to the appropriate energies and that a long flight path through the cell must be provided to increase the likelihood that each ion experiences several collisions in fransit. The construction and operation of low energy CID cells are described, for example, in U.S. Pat No. 5,248,875 to Douglas, et al. and Thomson et al., "Experimental Collision Cell for the API III," Research Report KE109202, PE Sciex (now a division of Applied Biosystems), 1992. Such cells are commercially available, for example, as integral components of complete mass spectrometer systems manufactured by Applied Biosystems (Foster City, CA), Bruker Daltonics (Billerica, MA), Kratos Analytical (Chestnut Ridge, NY), Micromass, Ltd. (Manchester, UK), and Thermo Finnigan (San Jose, CA), or as stand-alone units manufactured by ABB Exfrel (Pittsburgh, PA). High energy CID cells are much simpler in design, basically consisting of a rectangular or cylindrical chamber into which the target gas is introduced and through which the ions can drift without the aid of electric or magnetic fields. Illustrations of such cells and descriptions of their use can be found, for example, in Bricker and Russell, Journal of the American Chemical Society, 108: 6174-6179, 1986 and Medzihradszky et ?λ.,=Analytical Chemistry, 72: 552-558, 2000.

Several approaches to constructing tandem TOF mass spectrometers have been taken. The earliest involved the use a high resolution TOF mass analyzer or a double-focusing sector mass analyzer for MSI and a high resolution TOF mass analyzer as MS2. Although it was demonstrated that such configurations could produce product-ion mass spectra at unit mass-resolution or better, this index of performance was offset by the fact that the instruments were also less sensitive than a single TOF mass analyzer, large, complicated to operate, and expensive. Recently however, two forms of tandem TOF mass spectrometers have emerged independently to set new standards for qualitative mass spectrometry. The first of these is a hybrid configuration that combines the power of quadrupole and TOF analyzers (Q-TOF) [Dodonov, Chernushevich, Dodonova, Raznikov, and Tal'roze, USSR Patent No. 1681340A1 , February 1987; Mirgorodskaya et al., Analytical Chemistry, 66: 99-107, 1994; Nerentchikov et al., Analytical Chemistry, 66: 126- 133, 1994; Morris et al., Rapid Communications in Mass Spectrometry, 10, 889-896, 1996; Shevchenko et al., Rapid Communications in Mass Spectrometry, 11, 1015- 1024, 1997; Krutchinsky et al., Rapid Communications in Mass Spectrometry, 12, 508-518, 1998; Smimov et al., in Proceedings of The 47th ASMS Conference on Mass Spectrometry and Allied Topics, Dallas, TX, 1999; Cotter, Analytical Chemistry, 71, 445A-451A, 1999; Chernushevich et al., Analytical Chemistry, 71, 452A-461A, 1999; Blackburn et al., American Pharmaceutical Review, 2: 49-59, 1999; Lazar et al., American Laboratory (February), 110-119, 2000; Nerentchikov et al., in Proceedings of The 48th ASMS Conference on Mass Spectrometry and Allied Topics, Long Beach, CA, 2000; Guilhaus et al., Mass Spectrometry Reviews, 19, 65- 107, 2000.]. The Q-TOF geometry, which can be used with electrospray ionization (ESI), matrix-assisted laser desorption/iomzation (MALDI), and other ionization processes, selects precursor-ions with a high-performance quadrupole mass filter, fragments them via low-energy CID, and analyzes the product-ions with a high mass resolving power (ml Am ≥ 7,000), high mass accuracy (~5 ppm), high sensitivity (femtomole levels) TOF mass analyzer. Q-TOF systems can greatly reduce ambiguity in studies involving identification of metabolites or discovery of natural products. The excellent sensitivity, speed, resolution, mass accuracy, and stabile mass calibration that the TOF analyzer brings to the Q-TOF configuration are particularly advantageous in protein research. Specifically, these instruments have the requisite sensitivity to detect proteins in 2-D gel spots, mass range to examine non-covalent interactions, resolution to distinguish among peptides of very similar molecular weights, and mass accuracy to unequivocally determine the charge states and elemental compositions of most tryptic peptides.

The second form of tandem mass spectrometer to appear recently is the tandem TOF (TOF/TOF) [Piyadasa et al, Rapid Communications in Mass Spectrometry, 12: 1655-1664, 1998; Vestal et al., An Improved Delayed Extraction MALDI-TOFfor PSD and CID, 46^th ASMS Conference on Mass Spectrometry and Allied Topics, Orlando, Florida, 1998; Katz and Barofsky, New Design for a MALDI Tandem Time-of-Flight Mass Spectrometer, 47^th ASMS Conference on Mass Spectrometry and Allied Topics, Dallas, Texas, 1999; Medzihradszky et al., Analytical Chemistry, 72: 552-558, 2000; Barofsky et al., Tandem Time-of Flight Mass Spectrometer, U.S. Patent Application No. 09/405,208; Vestal, A Tandem Time-of-Flight Mass Spectrometer with Delayed Extraction and Method for Use, U.S. Patent No. 6,348,688; U.S. Provisional Patent Application No. 60/386,134]. The TOF/TOF geometry, which may be used with MALDI, selects precursor-ions by taking advantage of the inverse dependence of their velocities in the constant energy mode on the square root of their masses, fragments them via high-energy CJ-D, and after subjecting them to a second stage of acceleration, analyzes the product-ions with a high mass resolving power (ml Am > 7,000), high mass accuracy (~5 ppm), high sensitivity (femtomole levels) TOF mass analyzer. The novel design and operation of the velocity-selector used in MSI makes it possible to routinely choose precursors at resolving powers up to 700. Accelerating the product-ions to energies greater than 20,000 eV prior to analyzing them in MS2 makes it possible to achieve high resolution mass spectra that cover the entire mass range of the product- ions and their precursor-ion without stepping the ion-reflector's voltage (which is an exceptionally inefficient, tedious, manual form of scanning). Both of these features are achieved while retaining the advantages of sensitivity, unlimited mass range, and nonscanning data acquisition inherent to TOF mass analyzers.

In a time-of-flight (TOF) mass spectrometer, the times for ions of various masses to travel a given distance in field free space are measured. In an ideal situation, the ions in a set being subjected to TOF analysis would have been caused to originate at the same time from a single plane in space and, subsequently, to acquire velocities that depend strictly on their respective masses. In any real situation, the ions selected for TOF analysis originate over a short span of time in a small volume of space and acquire velocities that have second and higher order dependencies on factors other than mass. The performance, i.e. mass resolution, mass accuracy, and sensitivity, of a TOF mass spectrometer is determined in large part by the degree to which it can conect for deviations from the conditions for ideal TOF analysis.

When an ion with mass m , charge q , and zero initial velocity is accelerated in a uniform, static electric field £ over a fixed distance d , the kinetic energy T it acquires is given by

T = y₂mv² = qEd .

Since the work qEd performed on the ion is independent of its mass, the kinetic energy gained in the field £ by any other ion accelerated from the same starting position over the distance d , inespective of its mass, would also be qEd (thus, the terminology 'constant energy acceleration mode'). It readily follows from the preceding equation that the ion's velocity v is

\2qEd v = m

and its time-of-flight t over a path length L is

Hence, a TOF mass spectrometer operating in this constant energy mode generates a mass spectrum whose mass scale is, to the first order, proportional to the square of flight-time, i.e. t^z . As previously stated, all TOF mass spectrometers being commercially built today operate in a constant energy mode. When an ion with mass m , charge q , and zero initial velocity is accelerated in a uniform, static electric field £ for a fixed time r , the momentum p it acquires is given by

p = mv = qEτ . Since the impulse qEτ performed on the ion is independent of its mass, the momentum gained in the field £ by any other ion accelerated from the same starting position over the distance d , irrespective of its mass, would also be qEτ (thus, the terminology 'constant momentum acceleration mode'). It readily follows from the preceding equation that the ion's velocity v is

qEτ v = m

and its time-of-flight t over a path length L is

t ~ — = m ∞ m v qEτ

Hence, a TOF mass spectrometer operating in this constant momentum mode generates a mass spectrum whose mass scale is to the first order linearly proportional to the flight-time t . Because the relationship between time and mass under constant momentum acceleration is linear, the mass resolving power for any given mass m in the constant momentum mode (R = m/Am = t/At ) is double the mass resolving power in the constant energy mode ( R = m/Am = A ¹ t/At ). Constant momentum TOF MS was first demonstrated in 1953 [Wolff and Stephens, The Review of Scientific Instruments, 24: 616-617, 1953]. However, since that time, its use has been discussed in the literature only on a few occasions and only from theoretical perspectives [Poschenrieder, International Journal of Mass Spectrometry and Ion Physics, 6: 413, 1971; loanoviciu, Rapid Communications in Mass Spectrometry, 12: 1925-1927, 1998; loanoviciu, Nuclear Instruments and Methods in Physics Research A, 427: 157-160, 1999]. Presently, no working embodiment of a TOF mass spectrometer based on constant momentum acceleration appears to be commercially available.

When ions originate on one of the electrodes of a single-stage accelerator as shown in Figure la or lb, for example, by inadiating a sample with a pulse of photons from a laser, or bombarding a sample with keV or MeV particles, they have narrow initial time and position distributions, but a broad, weakly mass dependent initial velocity distribution in the direction of acceleration. When ions are produced in an external ion source, for example by ESI, atmospheric chemical ionization, atmospheric or high pressure MALDI, electron impact ionization, or chemical ionization, and are then transported into the acceleration region as shown in FIG. lb or Id, they have narrow initial time and velocity distributions, but a broad spatial distribution in the direction of acceleration.

Correction for either the wide velocity distribution that results when ions originate on an acceleration electrode (FIGS, la and lc), or the wide spatial distribution when they are transported into the acceleration space from an external source (FIGS, lb and Id), can be achieved by using two stages of acceleration in an electrode configuration like that shown in FIG. 2. Typically, the first electric field, which is periodically switched on and off to repeatedly extract ensembles of ions, is relatively low while the second electric field, which is on continuously, is relatively high. Spacings between the acceleration electrodes and phasing of the accelerating field's switching times vary in actual embodiments, depending on whether the dual- stage accelerator is being used to conect for an initial velocity or spatial distribution. Treatments of the principle and design of dual-stage accelerators can be found in the general mass specfrometry literature [Wiley and McLaren, The Review of Scientific Instruments, 26: 1150-1157, 1955; Cotter, Time-of-Flight Mass Spectrometry, American Chemical Society: Washington, DC, 1997; Chapter 2; loanoviciu, Rapid Communications in Mass Spectrometry, 9, 985-997, 1995].

It is impossible to correct for an initial distribution of velocities or starting positions using constant momentum acceleration in a uniform electric field because the kinetic energies of all ions of the same mass are increased by exactly the same amount (viz. {qEτ) /2m ) regardless of their initial starting positions. Use of a two-stage ion reflector has been proposed as a means for conecting an initial velocity distribution in a homogeneous single-field ion source operated in a constant momentum acceleration mode [loanoviciu, Nuclear Instruments and Methods in Physics Research __, 427: 157-160, 1999], but no practical device appears to have been built. An alternative to using acceleration in uniform electric fields to correct for an initial distribution in velocity or space is to use acceleration in an electric field that decreases continuously in strength along the direction of the ions' motion. A uniform electric field is characterized mathematically by a zero curvature in the electric potential distribution, i.e. by a derivative with respect to a given direction dE/dx that equals zero, whereas a decreasing electric field (dE/dx <0) is characterized by nonzero curvature in the electric potential distribution. Methods for using a decreasing electric field to improve mass resolution have been described in conjunction with a constant energy mode (a sigmoidal field combined with a uniform field) [Gardner and Holland, Journal of the American Society for Mass Spectrometry, 10: 1067-1073, 1999] and separately in conjunction with a constant momentum mode (a hyperbolic field) [loanoviciu, Rapid Communications in Mass Spectrometry, 12: 1925-1927, 1998; loanoviciu, Nuclear Instruments and Methods in Physics Research A, 427: 157-160, 1999]. loanoviciu theoretically demonstrated that a modified quadrupole frap might serve as a velocity-focusing ion source of ions accelerated to constant momentum. The quadrupolar arrangement of electrodes in the ion source described by loanoviciu was not disclosed to provide space-focusing of ions, and by virtue of its geometry would not permit operation in both constant energy and constant momentum modes. Until now, no instrument capable of space- focusing ions in both constant energy and constant momentum modes has been described, and no TOF instrument that may be operated in a constant momentum mode has been demonstrated.

Summary Accelerating ions in a decreasing electric field (dE/dx < 0) along the path of acceleration is disclosed to provide space-focusing of ions, regardless of whether the ions are accelerated to constant momentum or constant energy. Thus, a method for space-focusing ions accelerated to constant momentum is disclosed to include accelerating ions in a decreasing electric field with a negative gradient in the direction of acceleration. A time-of-flight (TOF) mass spectrometer is also disclosed that includes an ion source that accelerates ions through an electric field having a negative gradient in the direction of acceleration and focuses ions onto a space-focal plane, and an ion detector located at the space-focal plane. A TOF mass-analyzer is also provided where mass selection is based on the physics of accelerating ions to constant momentum, and reflecting ions having specific kinetic energies through an angle. In one embodiment, the disclosed mass-analyzer comprises two ion-optical devices ananged such that the electrodes in the first device produce ions having momenta nanowly distributed about a specific magnitude, and the electrodes in the second device transmit ions having kinetic energies narrowly distributed about a specific magnitude. A tandem TOF mass spectrometer is also provided with performance characteristics based on the energy- selecting properties of the disclosed mass-analyzer, and the mass-dispersive properties of an ion-reflecting TOF mass-analyzer. In one embodiment, a tandem mass spectrometer is provided by coupling the disclosed TOF mass analyzer to a second mass-analyzing stage that comprises an existing TOF mass spectrometer.

Brief Description of the Drawings

FIG. 1 is a diagram comparing constant energy and constant momentum acceleration of ions in axial and orthogonal extraction modes.

FIG. 2 is a diagram illustrating the components of a prior art, dual-stage ion accelerator. FIG. 3 is a diagram illustrating a working embodiment of a single-stage ion accelerator that is capable of providing space-focusing of ions in both constant- energy and constant-momentum modes.

FIG. 4 is a diagram showing one embodiment of a decreasing electric field ion accelerator/energy selector/TOF mass spectrometer. FIG. 5 is a diagram showing a decreasing electric field, ion accelerator/energy selector/TOF mass spectrometer coupled to a quadrupole mass spectrometer where the non-linear ion accelerator is configured for orthogonal extraction of ions received from the quadrupole device.

FIG. 6 is a diagram showing a decreasing electric field ion accelerator/energy selector/TOF mass spectrometer coupled to an existing TOF mass spectrometer to provide a tandem mass spectrometer. FIG. 7 is a mass spectrum of neurotensin (1672.9 Da), and its Sodium and Potassium adducts in both Constant Energy mode (left bunch of peaks) and Constant Momentum mode (right bunch of peaks).

FIG. 8 is an expanded view of amass spectrum of neurotensin (note isotopic distribution) using constant momentum acceleration in a decreasing electric field.

FIG. 9 is a mass spectrum showing isolation of a single isotope of Neurotensin using constant momentum acceleration in a decreasing electric field in combination with energy selection along a short flight path. Resolving power = 6,937. FIG. 10 is a mass spectrum showing isolation of a single isotope of

Neurotensin using constant momentum acceleration in a decreasing electric field in combination with energy selection and a longer flight path, including a pass through a single stage ion minor. Resolving power = 31 ,869.

Detailed Description

Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Definitions of common terms in mass spectrometry may be found, for example, amongst the references discussed in the Background. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. The term "comprises" means "includes." The terms "reflecfron," "reflector," and "ion reflector" are synonymous and refer to any single or plural stage, linear or non-linear reflecfron now in existence or developed in the future. As used herein, the term "downstream" refers to a position relative to a given component or action that is farther along a path that ions are traveling. Similarly, the term "upstream" refers to position relative to a given component or action that is prior to the component or action along the path that ions are traveling. h case of conflict, the present specification, including explanations of terms, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Various embodiments are illustrated by the following non-limiting Examples.

Examples A mass-selective device is provided that takes advantage of constant- momentum acceleration in order to increase the mass-resolving power of a TOF mass spectrometer. The mass selective device includes a decreasing electric field, single-stage ion accelerator (a particular working embodiment is shown in FIG. 3) that can be operated in either a constant energy or constant momentum mode, and an energy-selector TOF mass analyzer that can be used either as a stand-alone MALDI TOF mass spectrometer (a particular working embodiment is shown in FIG. 4), as the TOF analyzer in a hybrid Q-TOF mass spectrometer (a particular embodiment is shown in FIG. 5), or as the MSI -stage in a TOF/TOF mass spectrometer (a particular embodiment is shown in FIG. 6) The ion accelerator in FIG. 3 is characterized by its capacity to conect, in merely one stage of either constant-energy or constant-momentum acceleration, for an initial distribution in either the positions or the velocities of the ions selected for extraction. The energy-selector TOF mass analyzer shown in FIG. 4 is characterized by its capacity to change the m/z range of the transmitted ions continuously from ∞ to a single value while maintaining a very high resolving power. The latter feature makes it possible to use the energy-selector TOF mass analyzer (without sacrificing any of the desirable qualities of sensitivity, resolving power, mass accuracy, and low-cost inherent to TOF mass spectrometers) as a component in either a hybrid Q-TOF geometry (see, for example, FIG. 5) or a TOF/TOF geometry (see, for example, FIG. 6). In these combinations, the energy selector TOF mass analyzer enables a number of analytical modes that are not presently possible on mass spectrometers of these types.

In one embodiment, an ion source is provided comprising an ion source that accelerates ions through an electric field having a negative gradient in the direction of acceleration and focuses ions onto a space-focal plane and a target located at the space-focal plane. The target may, for example be a conductive (for example, a metal or conductive polymer), a semiconductive (for example, silicon or gallium arsenide), or an insulating substrate (for example, a glass, a metal oxide, an insulating plastic or quartz). In a particular embodiment, a single stage ion source is provided, consisting essentially of a repeller electrode and an acceleration electrode, the repeller electrode and acceleration electrode configured to provide a negative gradient in the direction ions are accelerated, the ion source focusing ions onto a space-focal plane. The repeller electrode may serve as a sample stage from which ions are desorbed (e.g. as a MALDI sample stage). In more particular embodiments, the position of the space-focal plane is adjustable (e.g. by varying the electrode potentials and delay times between ion production and acceleration).

In another embodiment, a time of flight mass spectrometer is provided. The mass spectrometer may comprise an ion source, which accelerates ions through an electric field having a negative gradient in the direction of acceleration and focuses ions onto a space-focal plane, and an ion detector located at the space-focal plane. The mass spectrometer may also include an energy selector downstream of the ion source and upstream of the ion detector. I-n particular embodiments, the ion source may be a particle- or photon-induced desorption/ionization ion source (for example, a FAB or MALDI source; see, for example, FIG. 4), and in other embodiments, the ion source may be an ion source, which may an external ion source, that produces a stream of ions from which packets of ions are extracted from the stream through a field having a negative gradient in a direction orthogonal to the direction of the stream of ions (see, for example, FIGS. 1 and 5). The optional energy analyzer comprises, in particular embodiments, a pair of 90° retarding potential energy- analyzers (see, for example, FIG. 4), a pair of 180° retarding potential energy analyzers (see, for example, FIG. 5), or a pair of retarding potential energy analyzers set at any non zero angle less than 180°. In other embodiments, a time-of-flight mass spectrometer is provided comprising an ion source that accelerates ions through an electric field having a negative gradient in the direction of acceleration and focuses ions onto a first space- focal plane, a reflectron downstream of the energy selector that defines an object plane located at the first space-focal plane and focuses ions onto a second space- focal plane, and a detector located at the second space-focal plane. As before, the ion source may be a particle- or photon-induced desorption/ionization source or an ion source, which may be an external ion source, used in conjunction with orthogonal extraction. The mass spectrometer may also include an energy selector such as a pair of either 90° or 180° retarding potential energy-analyzers. In more particular embodiments, the mass spectrometer also includes a dissociation cell downstream from the energy selector and a linear ion accelerator downstream from the dissociation cell that focuses ions onto a second space-focal plane. In such embodiments, the reflectron downstream of the energy selector defines an object plane located at the second space- focal plane and focuses ions onto a third space- focal plane.

As another aspect, methods are provided for producing beams of ions having constant energy or constant momentum that are space-focused onto a target. These methods include accelerating ions to constant energy in an electric field, the electric field having a negative gradient with respect to a flight path along which the ions are accelerated, and space-focusing ions onto the target.

In some embodiments, methods for obtaining mass spectra are provided. Such methods may include ionizing a material to produce a set of ions, accelerating the set of ions to constant momentum or constant energy in an electric field, the electric field having a negative gradient with respect to a flight path along which the ions are accelerated, space-focusing at least a portion of the ions onto a space-focal plane, allowing the set of ions to move along the flight path so that ions of different masses spatially separate along the flight path, and detecting at least a portion of the ions as they arrive at the space-focal plane. In other embodiments the methods further include reflecting the ions using a reflecfron, the reflectron having an object plane located at the first space-focal plane and focusing ions onto a second space- focal plane, and detecting at least a portion of the ions as they arrive at the second space-focal plane.

In other embodiments, methods are provided for obtaining a mass spectrum, the methods comprising ionizing a material to produce a first set of ions, accelerating the first set of ions to constant momentum (or constant energy) in an electric field, the electric field having a negative gradient with respect to a flight path along which the ions are accelerated, space-focusing ions onto a space-focal plane, allowing the set of ions to move along the flight path so that ions of different masses spatially separate along the flight path, selecting a portion of the first set of ions having a mass-dependent energy less than a first threshold energy to produce a second set of ions, selecting a portion of the second set of ions having a mass- dependent energy greater than a second threshold energy to produce a third set of ions, the second threshold energy being lower than the first threshold energy, and detecting at least a portion of the third set of ions as they arrive at the first space- focal plane. In particular embodiments, the methods further include reflecting the ions focused by acceleration in the non-linear field using a reflectron, the reflectron having an object plane located at the first space-focal plane, space-focusing ions onto a second space-focal plane, and detecting at least a portion of the third set of ions as they arrive at the second space-focal plane. In more particular embodiments, the methods also may include inducing dissociation of at least a portion of the third set of ions to produce a fourth set of ions, accelerating the fourth set of ions to constant energy so that at least a portion of the fourth set of ions is focused onto a second space-focal plane, reflecting the fourth set of ions using a reflectron, the reflectron having an object plane located at the second space-focal plane, space- focusing ions onto a third space-focal plane, and detecting at least a portion of the fourth set of ions as they arrive at the third space-focal plane.

Example 1 - Decreasing Electric Field, Single-Stage Accelerator The nonlinear field accelerator of FIG. 3 comprises a repeller plate 300 to which voltage pulse 302 may applied. An extraction region 304 is formed between repeller plate 300 and exit grid 306. The length of the extraction region, d, is defined by distance 308 between repeller plate 300 and exit grid 306. Exit grid 306 is electrically connected to earthed acceleration electrode 310. Optical axis Ai is normal to repeller plate 300 and passes through exit grid 306.

With reference to FIG. 3, voltage pulse 302 may be adjusted to a width as described above with reference to FIG. 1 to provide either constant energy or constant momentum acceleration. When the voltage pulse 302 is applied to repeller plate 300, sample ions (for example, passing parallel to the surface of repeller plate 300 or desorbed from the surface of repeller plate 300 by ionizing particles or photons) are accelerated in extraction region 304 toward exit grid 308. The shape of earthed acceleration electrode 310 is such that the strength of an electric field decreases non-linearly along optical axis Ai.

A working embodiment of the nonlinear field accelerator of FIG. 3, where d = 0.06 m, was built and tested in the MALDI mode. However, the distance between the repeller plate and the acceleration electrode may, for example, be established arbitrarily if the electric field gradient of the electric field remains negative. For example, C. may vary from about 0.001 m to about 1.0 m, such as from about 0.01 m to about 0.10 m. The radius of curvature of the accelerating electrode may also be varied arbitrarily, again as long as the resultant electric field retains the negative gradient that provides space-focusing of ions. The system's ion source can effect ionization and volatilization by any mechanism; the only requirement imposed on any ion source to be used with the system shown in FIG. 3 is that the ions be generated in the plane of the sample plate (as would be the case, for example, with any pulsed laser or particle induced desorption/ionization process such as MALDI or FAB), or that the ions be introduced into the extraction region along an axis that lies in the plane of repeller plate 300 (as would be the case, for example, with any continuous or quasi continuous ionization process, such as ESI, atmospheric chemical ionization, atmospheric or high pressure MALDI, electron impact ionization, or chemical ionization). The space-focal planes and/or the velocity-focal plane may be adjusted by varying the accelerating voltage and/or the delay time between creation/introduction of ions into the extraction region, and application of the accelerating pulse.

The essence of the disclosed decreasing electric field ion accelerator devices, and the particular working embodiment shown in FIG. 3, lies not in its particular geometry, but rather in the negative gradient of the electric field it creates. In theory, there are an infinite number of electrode geometries that can be used to produce a decreasing electric field, i.e. a field for which dE/dx < 0 ; although in practice, those geometries that have strong curvature in the vicinity of the repeller plate are more likely to prove practical. The disclosed accelerator is based in part on the discovery that any pair of electrodes, regardless of shape, spacing, or dimension, that creates an electric field with a negative gradient can, in principle, be used as a single-stage accelerator for space-focusing ions both in a constant energy and constant momentum mode or for velocity-focusing in a constant momentum mode. The change of mode from constant energy to constant momentum or vice versa is possible at any time before or during operation. Alternatives to the electrode configuration shown in FIG. 3 (i.e. different electrode shapes, spacings, dimensions, etc.) that provide the requisite negative gradient of the electric field, are within the scope of the disclosure. For example, repeller plates of various shapes including curved and flat repeller plates, and acceleration electrodes of circular, parabolic, and hyperbolic geometries are possible, as long as they provide the requisite negative gradient of the electric field. The particular anangement of electrodes shown in the working embodiment of FIG. 3 is capable of accelerating ions, which may originate either with an initial velocity distribution from the plane of the repeller plate or with an initial spatial distribution from a continuous beam entering the accelerator orthogonal to the optical axis, so that the extracted ions are space-focused onto a plane in a field free region outside the accelerator. In the particular geometry of FIG. 3, the electric field in the near vicinity of the repeller plate has a pronounced negative gradient, i.e. dE/dx « 0. Switching between constant energy and constant momentum modes is achieved simply by changing the duration of the voltage pulse applied to the repeller plate. If the extraction pulse is on when the last of the ions pass through the exit grid into the field free region, they will acquire constant energies, but if the extraction pulse is turned off before any of the ions reach the exit grid, they will acquire constant momenta.

Example 2 - Energy-Selector TOF Mass Analyzers

A particular working embodiment of the disclosed mass spectrometer systems is shown in FIG. 4. In this embodiment, nonlinear field accelerator 400 (of the design shown in FIG. 3 with d=0.06 m) is shown schematically as comprising repeller plate 402 and acceleration electrode 404, although it is to be understood that the configuration of these electrodes is such that a negative electric field gradient is established as already discussed. Desorbing/Ionizing radiation beam 406 (such as a laser or fast atom source) is directed onto repeller plate 402 onto which a sample is loaded. Voltage pulse 408 is applied as already described with respect to FIGS. 1 and 3 to provide either constant momentum or constant energy acceleration of the ions desorbed from repeller plate 402 by desorbing/ionizing radiation beam 406. hi the working embodiment of FIG. 4, ions were produced by a MALDI process. Downstream of nonlinear field accelerator 400 is energy analyzer 410 which comprises a pair of 90° retarding potential energy-analyzers 412. Located downstream of energy analyzer 410, and along the path ions are accelerated from non-linear accelerator 400, is 1^st straight mode detector 414. Located along a path that is orthogonal to the path ions are accelerated from non-linear accelerator 400, and downstream from energy analyzer 410, are reflector 416, 2^nd straight mode detector 418 and reflector mode detector 420.

In the 90° configuration energy analyzer shown in FIG. 4, the first retarding potential energy analyzer 412 that ions encounter acts as a high-energy cut-off filter. Ions with energies greater than 2qV_R1 , where q is the charge on an ion and V_R1 is the voltage applied to the analyzer's retarding grid, pass through the analyzer and strike the 1^st straight detector 414, and ions with energy less than 2qV_R are reflected through 90° toward the second retarding potential energy analyzer 412 that is downstream from the first. The second, downstream, retarding potential energy analyzer 412 acts as a low-energy cut-off filter in which all ions with energies less than 2qV_R2 , where V_R2 is the voltage applied to the analyzer's retarding grid, are reflected through 90° and off the flight-path of the TOF section. Ions with energies greater than 2qV_R2 pass through the analyzer into the TOF section, which in this embodiment includes reflector 416, 2^nd straight mode detector 418 and reflector mode detector 420. The operation of the TOF section is well-known to those of ordinary skill in the art.

FIG. 5 shows an alternative embodiment that includes an energy analyzer having a 180° configuration. Ion source 500 provides a stream of ions that first passes through interface optics 502, and downstream from interface optics 502 is gas collision cell 506. Operation of these components is well known. Downstream of gas collision cell 506 is nonlinear field accelerator 508, which comprises repeller plate 510 and acceleration electrode 512, which are configured to provide a negative electric field gradient orthogonal to optical axis A₂. Voltage pulse 514 is applied to repeller plate 510 to accelerate ions into energy analyzer 516, which comprises a pair of 180° retarding potential energy analyzers 518. hi the 180° configuration, the first analyzer acts as the low-energy cut-off filter, and the second, downstream analyzer acts as the high-energy cut-off filter. Downstream of energy analyzer 510, in the TOF section of the instrument, are 1^st sfraight detector 520, reflector 522, 2^nd straight detector 524 and reflector mode detector 526. Operation of the TOF section of the instrument is well known.

In both the 90° and the 180° configurations (and other configurations with non zero angles between 0° and 180°), the two energy filters operating in tandem form an energy selector with an energy window equal to 2q\ V_R1 - V_R21 that can easily be made arbitrarily wide or nanow by adjusting the absolute difference between the voltages. An energy window of a given width can be centered on any energy in the range of the extracted ions by simultaneously adjusting the two retarding voltages V_R and V_R2 so that their absolute difference remains constant. Another embodiment including a 90° configuration energy analyzer is shown in FIG. 6. This embodiment is a TOF/TOF instrument that includes nonlinear field accelerator 600, which comprises repeller plate 602 and acceleration electrode 604 configured to provide a negative electric field gradient along the direction in which ions are accelerated. In this embodiment, desorbing. ionizing radiation beam 606 (for example, photons or fast atoms) is directed to repeller plate 602 to desorb and ionize a sample that may be placed on the repeller plate 602. A voltage pulse 608 is applied to repeller plate 602 to accelerate ions either to constant energy or constant momentum as previously described. Downstream from nonlinear field accelerator 600 is energy analyzer 610 which comprises a pair of 90° retarding potential energy- analyzers 612 that may be operated as previously described. 1^st straight detector 614 is located downstream from energy analyzer 610 along a path that ions follow when accelerated by nonlinear field accelerator 600. Downstream of energy analyzer 610, and along a path orthogonal to the path that ions follow when accelerated by nonlinear field accelerator 600, are gas collision cell 616, linear ion accelerator 618, reflector 620, 2^nd sfraight detector 622 and reflector mode detector 624. Operation of the TOF system downstream of energy analyzer 610 is well known. The combined nonlinear ion accelerator/energy-selector/TOF system can be operated in a variety of novel modes that were discussed previously at the beginning of the examples. J-n the working 90° configuration diagramed in FIG. 4, operating the MALDI ion source in the constant energy mode and applying a retarding voltage to the first retarding energy analyzer that is slightly greater than y₂ V_accel , where

V_acce; is the magnitude of the accelerating voltage pulse used in the ion source, the system becomes a conventional MALDI TOF mass spectrometer. Switching the MALDI ion source over to the constant momentum mode without changing the energy analyzer's voltage doubles the mass resolving power of the system and converts its mass scale into one that depends linearly on time. If, while operating the MALDI source in the constant momentum mode, the energy selector is narrowly tuned to the energy conesponding to a particular mass, the system can produce an exceptionally high resolution mass spectrum of the selected ion species (See, for example, FIG 9). The 90° energy-selector is less compatible with orthogonal extraction geometries because the ion beam has a substantial velocity component that is orthogonal to the direction of ion extraction, leading to a loss of resolving power. Therefore, a 180° energy-selector may be used for a hybrid Q-TOF mass spectrometer, such as the one diagramed in FIG. 5. Using the constant energy mode to perform orthogonal extraction in this configuration, the system operates the same as any other conventional Q-TOF mass spectrometer. Performing orthogonal extraction in the constant momentum mode increases the system's resolving power by a factor of two. This capability is especially beneficial for tandem mass spectrometric mass analyses. In the TOF/TOF configuration shown in FIG. 6, all of the acceleration/focusing modes described for the system shown in FIG. 4 are available. Operating the MALDI source in the constant momentum mode with the energy selector set to a nanow energy window permits selection of a precursor ion at very high resolution for subsequent high-energy collision induced dissociation tandem mass spectrometric analysis. The configuration therefore obviates the need for the complicated timing and high- voltage switching circuitry that is required for the velocity-selector TOF/TOF systems, while greatly increasing both the transmission and the resolution of the first mass analyzer.

The unique combination of constant momentum acceleration and retarding potential energy selection to create a high resolution mass selector may be used in a variety of mass spectrometric systems as well as in fundamental ion beam studies. For example, any number of conceivable configurations of quadrupoles or methods of operating a configuration of quadrupoles may be used in combination with the disclosed nonlinear ion accelerator/energy selector/TOF mass spectrometer systems to provide hybrid Q-TOF mass spectrometers. Furthermore, the disclosed nonlinear ion accelerator/energy selector/TOF mass spectrometer systems are also compatible with any number of configurations of known TOF analyzers or method of operating a configuration of TOF analyzers that might be used as the MS2-stage (or higher) in a TOF/TOF mass spectrometer (more generally MSⁿ systems).

Example 3 - Mass Spectra of Neurotensin

Using the working embodiment of FIG. 4, neurotensin ions with a mass of 1,672.1 u were space-focused in the constant energy mode at the plane of a detector placed on the optical axis 0.35 m from the exit grid (see FIG. 3) by applying an acceleration potential of 6,000 V to the repeller plate 821 ns after each laser pulse was fired at the sample. In the constant momentum mode, space-focusing of the neurotensin ions onto the plane of the detector was achieved by shortening the duration of the 6,000 V acceleration potential to 3,500 ns and the delay after the each laser pulse to 1,800 ns. For ions having the same mass, the nonlinear electric field created by the geometry shown in FIG. 3 can be used to reduce the velocity distribution in the field free region nearly to zero. For example, velocity-focusing of neurotensin ions was achieved with the prototypic working embodiment by decreasing the delay of the 6,000 V high, 3,500 ns long acceleration pulse to 1,525 ns.

FIG. 7 shows the mass spectra of Neurotensin (1,672.9 Da) and its Sodium and Potassium adducts in both Constant Energy mode (left bunch of peaks) and Constant Momentum mode (right bunch of peaks). The resolving power of Neurotensin in this spectrum for constant energy mode was 410, whereas the resolving power in constant momentum mode was 871, a 112% increase in resolving power between the two modes.

FIG. 8 shows an expanded view of a mass spectrum of neurotensin produced in the constant momentum mode that illustrates the ability of the disclosed systems to resolve the isotopic distribution, a capability that is important, for example, when using mass spectromefry to sequence biopolymers.

Using the energy selector of FIG. 4 in combination with acceleration in a decreasing electric field permits isolation of individual isotopic peaks. FIG. 9 shows a mass spectrum of an isolated, single isotope of Neurotensin using constant momentum acceleration in a decreasing electric field in combination with energy selection along a short flight path (i.e. ions are detected at the 1^st straight detector of FIG. 4). fri this instance, the resolving power observed was 6,937.

Use of the reflector portion of the device shown in FIG. 4 permits even greater resolution. FIG. 10 is a mass spectrum showing isolation of a single isotope of Neurotensin using constant momentum acceleration in a decreasing electric field in combination with energy selection and a longer flight path, including a pass through a single stage ion minor (i.e., the ions are detected at the reflector mode detector of FIG. 4). h this instance, the resolving power was 31,869.

In view of the many possible embodiments to which the principles of our invention may be applied, it should be recognized that the illustrated embodiments are only examples of the invention and should not be taken as a limitation on the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention, all that comes within the scope and spirit of these claims.

Claims

We Claim:

1. An ion source, comprising: an ion source that accelerates ions through an electric field having a negative gradient in the direction of acceleration and focuses ions onto a space-focal plane; and a target located at the space-focal plane.

2. A time of flight mass spectrometer, comprising: an ion source that accelerates ions through an electric field having a negative gradient in the direction of acceleration and focuses ions onto a space-focal plane; and an ion detector located at the space-focal plane.

3. The mass spectrometer of claim 2 further comprising an energy selector downstream of the ion source and upstream of the ion detector.

4. The mass spectrometer of claim 3, wherein the ion source comprises a particle- or photon-induced desorption/ionization source.

5. The mass spectrometer of claim 4, wherein the energy selector comprises a pair of 90° retarding potential energy-analyzers.

6. The mass spectrometer of claim 3, wherem the ion source comprises an external ion source used in conjunction with orthogonal extraction.

7. The mass spectrometer of claim 6, wherein the energy selector comprises a pair of 180° retarding potential energy analyzers.

8. A time-of-flight mass spectrometer, comprising: an ion source that accelerates ions through an electric field having a negative gradient in the direction of acceleration and focuses ions onto a first space-focal plane; a reflectron downstream of the energy selector that defines an object plane located at the first space-focal plane and focuses ions onto a second space-focal plane; and a detector located at the second space-focal plane.

9. The mass spectrometer of claim 8, wherein the ion source comprises a particle- or photon-induced desorption/ionization source.

10. The mass spectrometer of claim 8, wherein the ion source comprises an external ion source used in conjunction with orthogonal extraction.

11. A time-of-flight mass spectrometer, comprising: an ion source that accelerates ions through an electric field having a negative gradient in the direction of acceleration and focuses ions onto a first space-focal plane; an energy selector downstream from the ion source; a reflectron downstream of the energy selector that defines an object plane located at the first space-focal plane and focuses ions onto a second space- focal plane; and a detector located at the second space-focal plane.

12. The mass spectrometer of claim 1, wherein the ion source comprises a particle- or photon-induced desorption/ionization source.

13. The mass spectrometer of claim 12, wherein the energy selector comprises a pair of 90° retarding potential energy-analyzers.

14. The mass spectrometer of claim 13, wherein the ion source comprises an external ion source used in conjunction with orthogonal extraction.

15. The mass spectrometer of claim 14, wherein the energy selector comprises a pair of 180° retarding potential energy analyzers.

16. A time-of-flight mass spectrometer, comprising: an ion source that accelerates ions through an electric field having a negative gradient in the direction of acceleration and focuses ions onto a first space- focal plane; an energy selector downstream from the ion source; a dissociation cell downstream from the energy selector; a linear ion accelerator downstream from the dissociation cell that focuses ions onto a second space-focal plane; a reflectron downstream of the energy selector that defines an obj ect plane located at the second space-focal plane and focuses ions onto a third space-focal plane; and a detector located at the third space-focal plane.

17. The mass spectrometer of claim 16, wherein the ion source comprises a particle- or photon-induced desorption/ionization source.

18. The mass spectrometer of claim 17, wherein the energy selector comprises a pair of 90° retarding potential energy-analyzers.

19. The mass spectrometer of claim 16, wherein the ion source comprises an external ion source used in conjunction with orthogonal extraction.

20. The mass spectrometer of claim 19, wherein the energy selector comprises a pair of 180° retarding potential energy analyzers.

21. A single stage ion source, consisting essentially of: a repeller electrode; and an acceleration electrode, the repeller electrode and acceleration electrode configured to provide a negative gradient in the direction ions are accelerated, the ion source focusing at least a portion of the accelerated onto a space-focal plane.

22. The ion source of claim 21 , wherein the repeller electrode is also a sample stage from which ions are desorbed.

23. The ion source of claim 21, wherem aposition of the space-focal plane is adjustable.

24. A method of producing a beam of ions having constant energy and space- focused onto a target comprising accelerating ions to constant energy in an electric field having a negative gradient with respect to a flight path along which the ions are accelerated to space-focus at least a portion of the accelerated ions onto the target.

25. A method of producing a beam of ions having constant momentum and space-focused onto a target comprising accelerating ions to constant momentum in an electric field having a negative gradient with respect to a flight path along which the ions are accelerated to space-focus at least a portion of the accelerated ions onto the target.

26. A method for obtaining a mass spectrum, comprising: ionizing a material to produce a set of ions; accelerating the set of ions to constant momentum in an electric field, the electric field having a negative gradient with respect to a flight path along which the ions are accelerated and space-focusing at least a portion of the accelerated ions onto a space-focal plane; allowing the set of ions to move along the flight path so that ions of different masses spatially separate along the flight path; and detecting at least a portion of the ions as they arrive at the space-focal plane.

27. A method for obtaining a mass spectrum, comprising: ionizing a material to produce a set of ions; accelerating the set of ions to constant energy in an electric field, the electric field having a negative gradient with respect to a flight path along which the ions are accelerated and space-focusing at least a portion of the ions onto a space-focal plane; allowing the set of ions to move along the flight path so that ions of different masses spatially separate along the flight path; and detecting at least a portion of the ions as they arrive at the space-focal plane.

28. A method for obtaining a mass spectrum, comprising: ionizing a material to produce a set of ions; accelerating the set of ions to constant momentum in an electric field, the electric field having a negative gradient with respect to a flight path along which the ions are accelerated and space-focusing at least a portion of the ions onto a first space-focal plane; allowing the set of ions to move along the flight path so that ions of different masses spatially separate along the flight path; reflecting the ions using a reflectron, the reflectron having an object plane located at the first space-focal plane and focusing at least a portion of the reflected ions onto a second space-focal plane; and detecting at least a portion of the ions as they arrive at the second space-focal plane.

29. A method for obtaining a mass spectrum, comprising: ionizing a material to produce a set of ions; accelerating the set of ions to constant energy in an electric field, the electric field having a negative gradient with respect to a flight path along which the ions are accelerated and space-focusing at least a portion of the accelerated ions onto a first space-focal plane; allowing the set of ions to move along the flight path so that ions of different masses spatially separate along the flight path; reflecting the ions using a reflectron, the reflectron having an object plane located at the first space- focal plane and focusing at least a portion of the reflected ions onto a second space-focal plane; and detecting at least a portion of the ions as they arrive at the second space-focal plane.

30. A method for obtaining a mass spectrum, comprising: - ionizing a material to produce a first set of ions; accelerating the first set of ions to constant momentum in an electric field, the electric field having a negative gradient with respect to a flight path along which the ions are accelerated and space-focusing at least a portion of the accelerated ions onto a space-focal plane; allowing the set of ions to move along the flight path so that ions of different masses spatially separate along the flight path; selecting a portion of the first set of ions having a mass-dependent energy less than a first threshold energy to produce a second set of ions; selecting a portion of the second set of ions having a mass-dependent energy greater than a second threshold energy to produce a third set of ions, the second threshold energy being lower than the first threshold energy; and detecting at least a portion of the third set of ions as they arrive at the space- focal plane.

31. A method for obtaining a mass spectrum, comprising: ionizing a material to produce a first set of ions; accelerating the first set of ions to constant energy in an electric field, the electric field having a negative gradient with respect to a flight path along which the ions are accelerated and space-focusing at least a portion of the accelerated ions onto a space-focal plane; allowing the set of ions to move along the flight path so that ions of different masses spatially separate along the flight path; selecting a portion of the first set of ions having a mass-dependent energy less than a first threshold energy to produce a second set of ions; selecting a portion of the second set of ions having a mass-dependent energy greater than a second threshold energy to produce a third set of ions, the second threshold energy being lower than the first threshold energy; and detecting at least a portion of the third set of ions as they arrive at the space- focal plane.

32. A method for obtaining a mass spectrum, comprising: ionizing a material to produce a first set of ions; accelerating the first set of ions to constant momentum in an electric field, the electric field having a negative gradient with respect to a flight path along which the ions are accelerated and space-focusing at least a portion of the accelerated ions onto a first space-focal plane; allowing the set of ions to move along the flight path so that ions of different masses spatially separate along the flight path; selecting a portion of the first set of ions having a mass-dependent energy less than a first threshold energy to produce a second set of ions; selecting a portion of the second set of ions having a mass-dependent energy greater than a second threshold energy to produce a third set of ions, the second threshold energy being lower than the first threshold energy; reflecting the third set of ions using a reflecfron, the reflectron having an object plane located at the first space-focal plane and space-focusing at least a portion of the reflected ions onto a second space-focal plane; and detecting at least a portion of the third set of ions as they arrive at the second space-focal plane.

33. A method for obtaining a mass spectrum, comprising: ionizing a material to produce a first set of ions; accelerating the first set of ions to constant energy in an electric field, the electric field having a negative gradient with respect to a flight path along which the ions are accelerated and space-focusing at least a portion of the accelerated ions onto a first space-focal plane; allowing the set of ions to move along the flight path so that ions of different masses spatially separate along the flight path; selecting a portion of the first set of ions having a mass-dependent energy less than a first threshold energy to produce a second set of ions; selecting a portion of the second set of ions having a mass-dependent energy greater than a second threshold energy to produce a third set of ions, the second threshold energy being lower than the first threshold energy; reflecting the third set of ions using a reflectron, the reflectron having an object plane located at the first space-focal plane and space-focusing at least a portion of the reflected ions onto a second space-focal plane; and detecting at least a portion of the third set of ions as they arrive at the second space-focal plane.

34. A method for obtaining a mass spectrum, comprising: ionizing a material to produce a first set of ions, accelerating the first set of ions to constant momentum in an electric field, the electric field having a negative gradient with respect to a flight path along which the first set of ions are accelerated and space-focusing at least a portion of the accelerated ions onto a first space- focal plane; allowing the first set of ions to move along the flight path so that ions of different masses spatially separate along the flight path; selecting a portion of the first set of ions having a mass-dependent energy less than a first threshold energy to produce a second set of ions; selecting a portion of the second set of ions having a mass-dependent energy greater than a second threshold energy to produce a third set of ions, the second threshold energy being lower than the first threshold energy; inducing dissociation of at least a portion of the third set of ions to produce a fourth set of ions; accelerating the fourth set of ions to constant energy so that at least a portion of the fourth set of ions is focused onto a second space-focal plane; reflecting the fourth set of ions using a reflecfron, the reflectron having an object plane located at the second space-focal plane and space-focusing at least a portion of the reflected ions onto a third space-focal plane; and detecting at least a portion of the fourth set of ions at the third space-focal plane.

35. A method for obtaining a mass spectrum, comprising: ionizing a material to produce a first set of ions, accelerating the first set of ions to constant energy in an electric field, the electric field having a negative gradient with respect to a flight path along which the first set of ions are accelerated and space-focusing at least a portion of the accelerated ions onto a first space-focal plane; allowing the first set of ions to move along the flight path so that ions of different masses spatially separate along the flight path; inducing dissociation of at least a portion of the third set of ions to produce a fourth set of ions; accelerating the fourth set of ions to constant energy so that at least a portion of the fourth set of ions is focused onto a second space-focal plane; reflecting the fourth set of ions using a reflectron, the reflectron having an object plane located at the second space-focal plane and space-focusing at least a portion of the reflected ions onto a third space-focal plane; and detecting at least a portion of the fourth set of ions at the third space-focal plane.