CA2526197C

CA2526197C - Multipole ion guide for mass spectrometry

Info

Publication number: CA2526197C
Application number: CA002526197A
Authority: CA
Inventors: Craig M. Whitehouse; Erol Gulcicek
Original assignee: Analytica of Branford Inc
Current assignee: Revvity Health Sciences Inc
Priority date: 1994-02-28
Filing date: 1995-02-27
Publication date: 2009-05-26
Anticipated expiration: 2015-02-27
Also published as: CA2526197A1

Abstract

A multipole ion guide which begins in one pumping stage and extends continuously into one or more subsequent pumping stages has been incorporated into an atmospheric pressure ion source mass spectrometer system. Ions delivered into vacuum from an electrospray, atmospheric pressure chemical ionization or inductively coupled plasma ion source are guided and focused into a mass analyzer with high efficiency using the multipole ion guide. The background pressure over a portion of the multipole ion guide length is high enough to cause kinetic energy cooling of ions traversing the ion guide length due to ion collisions with neutral background gas molecules. This ion kinetic energy cooling lowers energy spread of ions traversing the multipole ion guide length. The multipole ion guide DC offset potential can be used to adjust the mean ion energy and the ion guide a and q values can be set to reduce or expand the range of ion mass to charge which will be transmitted through the ion guide. These features of multipole ion guides and multiple pumping stage multipole ion guides are used to improve performance and lower the cost of atmospheric pressure ion source mass spectrometer instruments.

Description

CA 02526197 1995-02-27 .

Multlpole Ion wide fox Masx Spectrota~etry Field of Inycnt~n This .invention relates to the co~gura'on and method of using a multipole ion guide to transport and focus ions which enter vacuum from en .
atmvosphe~c pre$sure ion source, into a mass analyzer. The multipole inn guide which begins in one vacuwn pumping stage has been configured to.
extend continuously thra~ugh one or more subsequent vacuum stages.
Multlpole ion guides are used to efficiently -transfer ions through one or more vacuum stages while allowing the neutral background gas to be pumped away. The AC frequency arid AC and DC voltages which axe applied to the poles of a multipole ion guide can be set so that the multipole ion guide will pass a selected range of ion mass to charge. The ion tra~osmission properties of multlpole ion guides can be used to enhance performance of specif c mass analyzer types which ate interfhced to atmosphe~c pressure ion sources.
$acl~round vi the Iiayentivn Atmospheric pressure ion sources (API) hare 'become increasirngly importazit as. a means for generating ions used in mass analysis. Electrospray oz nebulization assisted Electrospray (ES), Atmospheric Pressure Chemical Ioniz$tion (APCI) and Inductively Coupled Plasma (ICP) ion sources produce ions from analyte species in a region which is approximately at atmospheric pressure. The ions must then be transported into vacuum for mass analysis.
A portion of the ions created in the API source are entrained in the bath gas API source chamber sad are swept into vacuum along with a the bath or carrier gas thxoqgh a~n orifice iuato vacuunn, Mass spectrometers (MS) generally operate in a vacuum maintained at between 10~' to 10'x° ton depending -oxi the mass analyzer type. The gas phase ions entering vacuunrt fx'om an A.FI source must be separated from the background cairiex gas and transported and focused through a single or ruultiple staged vacuum system into the mass analyzer. 'Variations in vacuum system and associated Z
electrostatic lens configurations have emerged in API/MS systems. Where multiple pumping stages have been er~xployed, the electrostatic lens elements have been configured to serve as restricted orifices between vacuum stages as well as providing ion acceleration and focusing oi:' ions into the mass analyzer. Performance tradeoffs may occur where electrostatic tenses must also accommodate restricting the neutral gas transmission from one pumping stage to the next. For example, a skimmer placed between one pumping stage and tl~e next may restrict the neutral gas flow but may also restrict the passage of ions as well due to its relatively small orifice size. Two types of ion lenses have been used to transport and focus ions in vacuum, particularly where-ions are entering vacuum fzom atmospheric pressure through a free jet expansion, The first is a static voltage lens and the second is a dynamic field ion guide, The most effective lens coztfigurations used in API/MS systems employ a judicious combination of both elements which have static and dynamic fields applied, The first ion lens type, an electrostatic lens, has a fxed or static DC
voltage applied during the time an ion is traversing the lenses' electric field.
Figure 1 is a diagrammatic representation of a four pumping stage API/MS system with static voltage electrostatic lenses, Gas emerging from the capillary exit 8 into vacuum expands as a supersonic free jet and a portion of the gas passes through the first 10 and second I4 skimmers. Skimmers between pumping stages typically have small orifices to restxact the neutral gas flow into each downstream vacuum stage, DC voltages are applied to the capillary exit, skimmers and other electrostatic lenses 9, 14, 15, 16 azad 17 with values set to rraaximize the ion transmission into the mass analyzer 18. Ions entrained in the expanding gas follow trajectories that are driven by a combination of electrostatic and gas dynamic forces, Strong influence from the gas dynamics can extend up to and beyond the second skimmer 13 for the configuration shown. in Figure 1. "the efficiency of ion transmission through a static voltage lens set can be reduced by scattering losses due to collisions between ions aad the background gas which occur along the ion trajectory.
Ions with different m/z ntay have different collisional cross sections and hence experience different numbers of background collisions as they are transported through vacuum. For a given electrostatic lens voltage setting, the efficiency of ion transport into the mass spectrometer may vary with m/z or the collisional cross section. Setting the lens voltage values to optimize transmission for a given ion species may not optimize transmission efficiency for another ion species. Static lens configurations used in API/MS
applications may not transmit lower molecular mass compounds as efficiently as higher molecular mass compounds. The smaller ions may sustain higher transmission losses due to collisional scattering from the background gas than tl~e higher molecular mass compounds, To increase ion transmission efficiency through a static lens stack, the electrostatic energy must be set sufficiently high so that low m/z ions can be driven through the background gas. Also, static voltage lens configuzatxo~as may focus ions of different energy at different focal points. Ions delivered into vacuum from an API
source produces an ion beam that may initially have different ion energies for different ion species present. If the focal point for a given ion is not located at the mass spectrometer entrance, transmission losses can occur. To overcome the mass to charge transmission discrimination effects and ion transport inefficiencies which occur when static voltage lenses are used, multipole dyz~atnic field ion guides have been employed to transport ions through vacuum pumping stages in the vacuum region of ApI/MS systems.
The dynamic electrostatic gelds within a multipole ion guide dominate over the background gas scattering collisions and effectively "trap" the ions while they traverse the length of the multipole ion guide.

The use of multipole ion guides has been shown to be an effective means of transporting ions through vacuum. Publications by Olivers et. al.(Anal, Chem, Vol. 59, p. 1230-1232, 1987), Smith ek, al, (Axial, Chem. Vol. 60, p.436-441, 1988) and U.S. patent number 4,963,736 havc reported the use of quadrupole ioz~ guide operated in the AC-only mode to transport ions from an API source Into a quadrupole mass analyzer. U.S. Patent 4,963,736 describes the use of a multipole ion guide in either vacuum pumping stage two of a three stage system or in the fast pumping stage of a two stage vanuum system, This patent also reports that increasing the background pressure up to 10 millitorr in the vacuum stage where the ion guide was positioned resulted izi an increase in ion transmission efficiency and a decrease in ion eziexgy spread of ions transmitted, Ion signal intensity decreased for background pressures higher than 6 millitorr iii the reported quadrupole conliguxation. A commercially available API/MS instrument manufactured by Sciex, a Canadian cozz~pany, incorporates a quadrupole ion guide operated in the AC-only mode located befoze the quadruple mass filter in a single stage vacuum system. Ions and neutral gas flowing into vacuum through an orifice in the API source enter the quadrupole AC-only ion guide. The ions are trapped from expanding in the radial direction by the AC quadrupole fields and are transmitted along the quadrupole ion guide rod length as the neutral gas is pumped away through the rod spacing. Ions exiting the quadrupole ion guide are focused into a quadrupole mass filter located in the same vacuum chamber. Neutral gas is pumped away by a high capacity cyro pump. Multiple quadrupole ion guides have been used to transport ions from API sources through multiple vacuum pumping stages and into a Fourier-Transform Ion Cytlotron Resonance mass analyzer. Beu et. al. (J. Am, Soc.
Mass Spectrom vol. 4. 546-556,.1993) have reported using three quadrvpole ion guides operated in the AC=ozily mode located in three consecutive vacuum pumping stages of a. fave pumping stage Eleetrospray Fourier-Transform Ion Cyclotron Resonance (FT-ICR) mass spectrometer instrument.
The multiple pumping stages are required to achieve operating pressures in the mass analyzer of less than 2 x 10'9 tort, Orifices mounted in the partitions between each vacuum pumping stage which restrict neutral gas conductance from one pumping stage to the next were located between consecutive quadrupole ion guides.
Over the past few years as API/MS system design has evolved, higher performance with lower system cost has been achieved by using multiple vacuum stages to remove the background gas while ion lens systems located in each vacuum stage accelerate and focus ions whith enter vacuum frpm atmospheric pressure into the mass analyzer. The type of mass analyzer to which an API source is interfaced places its unique demands on the ion 6ransport lens eonfigwations arid vacuum requirements ire the ion transport region between atmospheric pressure and the mass analyzer. Each mess analyzer type has an acceptable ion energy, ion energy spread and entrance astgular divergence which the upstream ion transport lens systerrr must satisfy when delivering ions to the entrance of a mass spectrometer. For example, a quadrupole mass analyzer can accept ions with axial translational energy generally below 40 electron volts whereas a magnetic sector mass spectrometer requires ions with thousands of volts of axial translational e~exgy.
Xn the preseztt inventaozt, a zl~ultipole ion guide is configured to increase the overall sensitivity of an APl/MS system while reducing instrument cost and complexity. In one embodiment of the present invention, a multipoIe ion guide is used to transport ions entering vacuum from an API source to Time-Of Flight (TOF) Ion Trap and F'T-ICR mass analyzers_ A range of ion mass to charge (m/z) can be e~ciently transmitted through a multipole ion guide provided the ion guide operating stability region is set to pass those values of mlz. If an ion with a given mass to charge ratio falls within the opexati;og.

stability region of a multipole ion guide, the ion will be effectively trapped from drifting to far in the off axis direction but is free to move in the direttion of ion guide axis, Zf the ion m/z falls outside the stability region, it will not have a stable trajectory and may not reach the exit end. Collisions between an ion and the background gas w~ithiri the multipole assembly can also effect the ion trajectory and the ion kinetic energy as the ion passes through the multipole ion guide. The background gas, if present at high enough pressure, may serve, through collisions, to dazrip the motion of ions as they pass through the ~nultipole ion guide, cooling their kinetic and thermal energy. This aids in forming an ion beam which exits the multipole iorx guide with reduced energy spread for a given ion species within the beam.
The stability region yr raztge of m/z which are transmitted through a multipole ion guide for a given background pressure environment can be varied by adjusting the AC frequency and AC and/or a DC voltage which can be applied with alternate polarity to each adjacent rod, The offset potential of the multipole lens, that is the DC voltage applied uniformly to all the rods on which the AC and alternate polarity DC rod potentials are floated and referenced is one variable that sari to be used to set the energy of ions transmitted through the multipole ion guide. The invention includes multipole ion guides configured to efficiently transport ions through a wide range of vacuum pressures. The ability of a multipole ion guide to deliver an ion beam into a mass analyzer with low energy spread where the rmean energy and m/z range is independently adjustable, can be used to improve the performance of API/Time-Of Flight, API/Ion Trap and API/FT~ICI2, mass spectxoxneter systems.
Another embodiment of the invention includes the incorporation of a multiple vacuum pumping stage multipole ion guide into an API/MS system, A
multiple vacuum pumping stage multipole ion guide is a multipole ion guide which begins in one pumping stage and extends continuously through oz~e or more additional vacuum pumping stages of a multiple pumping stage vacuum system. Multipole ion guides which are located in only oz~e vacuum pumping stage of a multiple pumping stage system must deliver the ions exiting the ion guide through an aperture dividing one purrxping stage from the next. If backgrouztd pressure is high enough to scatter the ions after the multipole ion guide exit of the aperture to the next pumping stage has a smaller diameter than the ion beam cross section, losses in ion transmission can occur. If individual multipole ion guides are located progressively in the first few pumping stages of an APl:/MS system, ion. transmission losses can occur when transferring ions between pumping stages, If fewer pumping stages are used to reduce the ion transmission losses between pumping Stages, the total gas flow and hence the total number of ions which can be delivered to vacuum may be compromised. Greater than 95% ion transmission efficiency can be achieved through multiple vacuum pumpih$ stages using multipole ion guides configured to extend continuously through more than one vacuum pumping stage. A multiple vacuum stage multipole ion guide must be configured serve as an ion guide having an internal open area small enough to minimize the neutral gas flow from one pumping stage to the next. Xu at.
el. (Nuclear Instx. and Ivlethods in Physics Research, Vol. 333, p. 274, 1.993) have developed a hexapole lens which extends through two vacuum pu~onping stages to transport ions formed in a helium discharge source operated in a chamber maintained at 75 to 150 torn of vacuum. A portion of the ions formed in the helium discharge souz'ce were swept into the next stage oaf vacuum through an orifice where they were transported through two additional vacuum stages usiztg a hexapole ion guide operated izi RF' oztly mode. Ions trapped by the ion guide were transported e~ciently through the two vacuum stages downstream of the source vacuutrt chamber, The baclcgrouzad pressure in the vacuum pumping stage dowrlstrea~n of the source g vacuum chamber was 600 millitorr followed by a vacuum stage with a background pressure of 9$ millitorr. Iozt transmission efficiencies through the hexapole ion guide beginning in vacuum stage one and extending unbroken into vacuum stage two were reported to be 90% for OT+. No mass spectrometer was used in the apparatus discussed by Xu at. el. and the helium discharge ion source background pressure in this apparatus was 5 to 10 times below atmospheric pressure arid helium was used as the background gas.
Different configuration and performance criteria exist for multiple pumping stage multipole ions guides incorporated into an Atmospheric Pressure Ion Sowce/Mass Spectrometer system than were requited for the_ ion guide application described by Xu and coworkers. Mulfiipole ion guides incorporated into APIIMS systems must have the capability of efficiently transmitting ions of various charge states over a wide range of mass to charge. Nitrogen, not helium, is typically used as cazrier gas in API sources and the background pressures in API/MS multiple vacuum stage systems are often very different from the pressures reported in the ion guide apparatus reported by Xu. An added constraint imposed on A,PI/MS systems which was not present in the non API/MS application practiced by Xu et, al. is the ability to fragment molecular ions by Collisional Induced Dissociation (CID) in the gas expansion region in the first two vacuum stages, Valuable structural information can be obtained from CiD of tuolecular ions produced in ES and APCI sources. CID conditions can be set by adjusting relative potentials between static voltage lenses and even the DC offset potentials of multipole ion guides located in the f rst twa vacuum pumping stages of a API
source, In the present invezttion, multiple pumping stage multipole ion guides are configured t~ maximi2e performance of A~PI/MS systems while reducing system vacuum pump cost, Increasing signal sensitivity while lowering vacuunn pumping cost is achieved by maximizing the ion ttat~sfer efficiency from the API source into the mass analyzer while minimizing the amount of neutral gas trans~erred. The invention describes multiple pumping stage multipole ion guides which begin in one vacuum pumping stage and extend unbroken through one or more subsequent pumping stages where the rod diameter and rod spaci~dg in the multipole ion guide assembly were configured small enough to mi.z~imize the transmission of neutral gas through the ion guide into downstream pumping stages. Acceptable vacuum pressure per pumping stage was be achieved with moderate capacity vacuum pumps.
The ion guide with a small irurier diameter was configured to allow suff cient conduction of neutzal gas tZlzough the spaces between the rods or poles so the neutral gas was pumped away e~~iciently in each pumping stage. Ef,Eicient iota trapping and transport through the ion guide was achieved over a wide range of background pressures along the ion guide length- The invention describes ion guides which tan be operated effectively at higher background pressures than API lMS ion guides reported in the literature listed above.
The small multipole ion guide inner diameters, described in oxle embodiment of the invention, produced an ion beam with a proportionally small cross section. The smaller cross section ion beam focused into the mass analyzer allowed the reduction of the mass analyzer entrance aperture without compromising ion transmission efficiency. Efficient ion transport, control of ion energy, decreased energy spread and a small beam diameter is achieved by using a multiple vacuum pumping stage multipole ion guide.
Summary of tl~e >lzwention In accordance with the present irtver~tion,, an Atmospheric Pressure Ion source which includes Electrospray or nebuli2ation assisted Electrospray, Atmospheric Pressure Chemical Ionization and Iziductively Coupled flasrn,a ion sources interfaced to a mass analyzer incorporates a multipole ion, guide 1~
in the vacuum pumping region between the API source and the mass azaalyzer.
In one embodiment of the invention, the API/MS system includes multiple vacuum pumping stages and a multipole ion guide which begins in one vacuum pumping stage and extends unbroken through two or more vacuum pumping stages. The multipole ion guide inner diameter is reduced to minimize the neutral gas conduction between vacuum pumping stages while allowing the efficient transport of ions through the multipole ion guide length.
At least one portion of a multiple vacuum, stage muldpole ion guide is subject to background gas pressures which ~e high enough that the ions traversing the ion guide length are subject to many collisions with neutral background gas molecules. Ion transmission efficiencies through such multipole ion guide assemblies can exceed 95 % even with background pressures in a given vacuum pumping stage of hundreds of millitorr. Collisions between the ions and the background neutral gas ire the multipole ion guide cause cooling of the ion kinetic energy, reducing the ion energy spread. The A,C field of the multipole ion guide traps lor~s within a radial cross sectioxi and prevents scattering losses of the ions undergoing collisions with the background gas as the ions traverse the ion guide length. 'The energy of the ions exiting the multipole ion guide relative to the mass analyzer entrance aperture potential can be set by varying the multipole ion guide DC oi~set potential. With sufficient ion kinetic energy cooling in the ion guide, ion e~aexgy can be adjusted over a wide range with little change to the ion energy spread for a given m/z. Ions with nnean energies of a few electron volts or lower cant be transmitted into the mass analyzer entrance aperture by using multiple vacuum pumping stage multipole ion guides. Lower eztergy ions with a narrow energy spread transmitted into quadrupole mass analyzers will result in higher Tesolution for a given sensitivity than can be achieved with higher energy ions. hacreased sexxsitivity and resplution can be achieved by using multiple vacuum pumping stage multipole ion guides with reduced vacuum system costs for quadrupole, time-of flight, ian trap, FT-XCR and magnetic sector mass spectrometers, When operating multipole ion guides in the AC only mode or with AC and DC applied to the poles, the frequency and voltage levels can be set ~so that a broad range of m/z ions will be transmitted through the multipole ion guide.
The AC frequency aztd AC and DC voltages can also be set to restrict the range of m/z values that will be transmitted through the multipole ion guide for a given background pressure environment. Narrowing the range of m/Z
values transmitted to the analyzer of a TOF mass spectrometer can be used to incxease the duty cycle and hence sensitivity of an AP1~TOF mass spectrometer instrument. Limiting the range of m/z for ions transmitted into an ion trap oz the analyzer cell of an FT-ICR mass spectrometer instrument can reduce the effects of space charging in the trap or FT-ICR cell during mass analysis. This can improve the mass measurement accuracy, resolution and dynamic range of the mass analyzer.
Description of the Drawinzs Figure 1 is a diagram of a four vacuum stage ES/MS quadrupole instrument with a static lens conf guratioz~ incorporated into vaouum stages I through 3.
Figure Z is a diagxam of a four vacuum stage ES/MS quadrupole instrument with a muldpole ion guide beginning iz~ the second vacuum pumping stage and extending continuously into the thixd pumping stage, Figure 3a shows the transno,ission e~ciency of ions through a two vacuum stage multipole ion guide fox m/z 110 over a range of values for q", Figure 36 shows the transmission efficiency of ions through a two vacuum stage multipole ion guide for m/z 872 over a range of values far ~".
Figure 3c shows the transmission efficiency of ions through a two vacuum stage multipole ior~ guide for m/z 1743 over a range of values for q".

Figure 4 is a mass spectrum of Glucagon witk~ the two vacuum pumping stage multipole ion guide q" value set to pass a wide range of m/z values.
Figure Sa is an Eleetrospray mass spectrum of Axgizune where the multipole ion guide q" value is set to pass a broad range of m/z values.
Figuxe Sb is a mass spectrum of Arginine where the rziuldpole ion guide q~
value is set so that a low mlx cutoff ion hansmission occuzs.
Figuxe 6a is an Electsospt'ay mass spectrum of Gramicidin S where tt~e raultipole ion guide q" value is set to pass a broad range of m/z values.
Figure 6b is a mass spectrum of Gramicidin, S where the multipole ion guide q" value is set so that a low m/z cutoff ion transmission occuxs.
Figure 7a is an Elcctrospray mass spectrum of a rm~ixture of A.rginir~e, Leucine Enkephalin acrd Granuicidin S where the multipole ian guide g" value is set to pass a broad range of m/z values.
Figure 7b is a mass spectrum of a mixture of Arginine, Leucine Enkephalin and Gramicidin S where the multipole ion guide g~ value is set so that a high m/x cutoff ion transmission occurs_ Figure 8a is a curve of ion signal for m/z 57I versus the multipole ion guide exit lens potential for a multipole ion guide DC offset potential set at 0.1 volts, Figure 8b is a curve of ion signal for zn/z 571 versus tlxe multipole ion guide exit lens potential fox a multipole ion guide DC offset potential set at 15.3 volts.
Figure $c is a curve of ion signal for mlz 571 versus the multipole ion guide exit leas potential for a multipole ion guide DC offset potential set at 25,1 volts.
p'igure 9 is a spectrum of a doubly charged Gramicidin S peals scanned with the m'~tltxpole ion guide offset potential set at 0.1 volt.

Figure 10 is a diagram, of a four vacuum stage ES/MS Time-OF-Flight instrument with orthogonal pulsiztg including a rnultipole ion guide beginning in the second vacuum pumping stage and extending into the third vacuum P~PinB stage, Figure 11 is a diagram of a three vacuum stage ES/MS ion trap instrument with a multipole ion guide beginning in the first vacuum stage and extending through the second and into the thiz~d vacuum pumping stages, Figure 12 is a cross section of a hexapole ion guide including the electrically itasulating mounting bracket.
Figure 13 is a diagram of a three vacuum pumping stage APIlMS ion trap instrument with a single pumping stage multipole ion guide located in th.e second vacuum stage.
Figure 14 is a diagram of a four vacuurrt pumping stage APIlorthogonal pulsing TOF mass spectrometer instrument with sizagle vacuum stage rnultipole ion guides located in the second and third vacuum stages.
Description of the Invention Sample bearing liquid is introduced into atmospheric pressure ionization sources including ES, APCI and ICP sources and gas phase ions are produced from the analyte in solution, API/MS systems are available which include from ox~e to over five vacuum pumping stages. An Electrospray ion source interfaced to a quadrupole mass spectrometer is diagrammed iz~ Figure 1.
The system. shown includes four vacuum pumping stages and a static voltage lens conf guration to transfer ions through the first three pumping stages and focus them into the entrance of quadrupole xt~,ass spectrometer 18. In the configuration shown, sample bearing liquid is introduced through needle 1 and is Electrosprayed into the bath gas in chamber 2, Liquid droplets evaporate in chamber 2 or as they are swept into vacuum through capillary 3 and ions are released from the evaporating droplets, The charged liquid droplets tan be dried by using a countercurrent drying gas 23 and/or a heated capillary 3. A portiozt of the ions and charged droplets formed in electrospray chamber 2 enter the capillary entrance 4 along with a portiozt of the background bath gas and are swept into vacuum thzough the capillary annulus 5. Alternatively the capillary or~ce into vacuum can be replaced by a nozzle with appropriate orifice size. The bath or carrier gas and entrained ions are swept through the capillary and enter ~tbe first vacuum stage 7 after passing through the capillary exit 8. The pressure in vacuum stage 7 is geaerally maintained between 0.4 and 20 tort so the gas exiting the capillary expands in a supersonic free jet. The ions entrained in this supersonic free jet are accelerated by collisions with the expanding background gas. The background gas used is usually niticogen but may be also be carbon dioxide, oxygen, helium or azty number of other gases which suit tbte analysis requirements and ion source type, An electzostatic field is applied between the capillary exit 8, the ring lens 9 and the first skinuner 10 to electrostatically focus and accelerate ions through the skimmer 10 orifice 11 and into the second vacuum stage 12. Vacuum stage 12 is typically operated at a pressure ranging from I to 200 millitorr dependiung ore pumping speeds and the size of skimmer orifice 11. Electrostatic potentials are maintained between skimmers 10 arid 13 and a portion of the ions passing through skimmer 10 are focused through orifice 22 in skimmer 13 into the third vacuum pumping stage 20. Pressure in puarping stage 20 is maintained typically between 1 x10' to below 8 x 10's tort. Potezttials are set on electrostatic lens elements 14, 15 anal 1,6 to focus ions through aperture 17 after whsch they pass into the quadrupole mass filter 18 located in the fourth pumping stage 24.
The static voltage lens system shown in Figure 1 transmits and focuses ions through the vacuum stages and into the mass analyzer while allowing the background gas to be pumped away. The ion energy relative to the quadrupole mass filter offset voltage is established by a combination of acceleration energy imparted by the expanding carrier gas and the electrostatic potentials applied. The capillary exit 8 potential relative to the ring electrode 9 axed skimmer electrode 10 cant be set high enough. to cause Collisional Induced Dissociation (CID) which may affect the energy and energy spread of the parent and fragment ions. Ion transmission losses can pecur in each pumping stage due to scattering from backgrouztd pressure and the inability to electxostatically focus all ions through the pumping stage skimmer orifices 11 and ?2 and the quadrupole entrance aperture 17. To achieve the desisted vacuum pressures per pumping stage, with vacuum pumping speeds lower than 800 L/sec per vacuum stage to reduce the vacuum pump cost and size, skimmer orifice 11 in this conFguration would typically have $ dianneter of 0.8 to 1.5 mm and skimmer orifice 22 may range from 0.8 to 3.0 mm, Depending on the mass analyzer pressure required, (10'6 tort fox quadrupoles and 10'' ton for magnetic sector analyzers) appropriate skimmers sizes can be selected to satisfy the vacuum requirements within the available pumping speed constraints, The smaller the skimmer orifice size the fewer the number of ions that can be transmitted through this static lens co~guration. The higher the ion energy spread for a given ro/z and the larger the energy difference fox ions with different m/z, tlae fewer the ions that can be effteiently focused izato the mass spectrometer and mass analyzed.
Depending ot~ vacuum pressures maintaibed during operation, the static lens cordiguratioz~ shown may exhibit different transmission efficiencies for different m/z values. Also, with static voltage lens systems, ion transmission efI'ieieney may drop off rapidly as the ioz~ energy is reduced below 10 electron volts.
To improve ion transzz~ission performance yet retain the advantages of multiple pumping stages to more cost e~'ectively remove neutral gas, a multipole ion guide has been used, replacing some of the, static voltage lenses. Figure 2 illustrates a multipole lens assembly ~0 which begins in .

vacuum pumping stage 41 and extends unbroken into vacuum pumping stage 42. Individual rods or poles 45 in assembly 40 are held in place and electrically isolated Carom the partition between vacuum pumping stage 41 and 42 by insulator 43, A cross section of a hexapole ion guide is illustrated in ~guxe 12 with insulator 156 serving the dual purpose ~f holdiztg. the six rods or poles 160 in position while miaimizing the effective aperture area inside the mds assembly diameter through which neutral gas flows and ions are tre~smitted from one pumping stage to tl~e next, . Multipole ion guide assembly 40 consists of parallel electrodes 45 in 1~igure 12 shown as round rods 160-equally spaced with a coenznon radius from the centerline. An octapole ion guide would have eight equally spaced rods and a quadrupole would have four equally spaced rods or poles, When multipole ion guide 40 is operated in the AC-only mode, every other rod has. the same .AC
frequency, voltage and phase and every adjacent rod ha_s the same AC
frequency - and voltage applied but a phase difference of 180 degrees: So for a hexapole ion guide, three rods or poles, (rods .1,3 at~d 5) would be opexated .
with the same AC frequency, voltage and phase and the same AC frequency and voltage with a pkrase difference of 180 degrees would be applied to the-remaining three rods (rods 2, 4 end 6). A DC offset voltage is applied to all rods 45 of the multipole ion guide 40 and plays a large role in establishing the ion energy. The skimmer47potential is set relative to the multipole ion guide DC offset potential to allow efficient transport of ions passing through slier 47 orifice 48 into the multipole ion guide 40. 'fhe kinetic energy of the ions entering multipole ion guide 40 includes contributions from the velocity innpartad by the expanding gas exiting capillary exit 50, tire xela've electxos'tatlc DC potentials applied to capillary exit.50, ring lens 51, skimmer 47 and the rnultipole rod 40 DC offset potezttial as well as any AC voltage component from hinging fields as ions enter multipole ion guide 40. Statio voltage lens elemetats 53 may be added at the exit end 52 of the multipole ion guide to focus ions into the mass analyzer entrance 47. Lens 53 is poaitio~ned at exit 52 of rnultipole lon guide 40 to shield the exiting ions from tha multipole A,C voltage fringhtg fields azid to focus the ions into the mass analyzer entrance aperture ~~ 9 The efficiency of ion transport through this two pumpizxg stage multlpole ion guide 40 is over 95°!o for a wide range of ion m/z values, Ion transmission ef~ciencios were determined by measuring the total ion current which passed thmugh skimmer orifice 48 sud by measuring the total ion current exiting multipole ion guide 40 for the same elcctrospray ion sourcs operating -conditions.
The quadrvpole mass analyzer shown for illustrati4n purposes in Figure 2 can be replaced by other mass analyzer types such as ion traps, TOF, FT-ICR and magnetic sector mass spectrometers. For mass analyzers which require ion energies of several kilovolts such as with magnetic sector mass spectrometers, the ion guide RF and DC potentials can be floated on kilovolt ion accelerating potentials. Although referenced to kilovolt accelerating potentials, the relative ion guide AC a~ad DC, skimmer 47 and -eacit lens 53 poteptials for a sector analyzer may. remain close to those used for Iow energy. mass analyzer co~'agurations such as in quadrupoles, ion guides, FT
ICR and TOF with flight tubes operated at ion accelerating poteiatials.
The performance characteristics of the two vacuum pumping stage rn~~ultipole ion guide 40 diagrammed in Figure 2 will be used as an example although many variations ins multiple pumping stage multipole ion guides are possible.
A.hexapole ion guide was configured with gods beg;Lttning in vacuum puxriping stage 41 and extending continuously into vacuum pumping stage 4a of a faun stage system as diagrammed in Figure 2. For testing purposes, the background pressures were varied in the first and second pumping stages 53 and 41, With multapole ion guilds 40 operated in the AC-only mode, the AC
frequency and amplitudd and the DC offset potentials were Varied to map out performance over a range of background pressures, A two vacuum stage hexapole ion guide was chosen over a qt~a~d~rupolc or octapole for the four vacuum stage API/MS system diagrarru~ed in figure 2 because the hexapole configuration was the most favorable compromise between trapping efficiency, vacuuzrt pumping conduction ttu~ough the rod spacing ~d overlap of stability regions for a wide range of mlz values and background pressures. Two non-dimensional coefficients aw and q" are commonly used when mapping ion trajectories in multipole ion guides or mass filters by solving the Laplace equatiozl of motion. The two coefficients are defined as:
n 3Y
an = n U and gn =
Z nz ~2r2 4 ni ~2r2 z 0 z 0 where n is the number of rod pairs (n=3 for a hexapole), U is the DC
potential applied to the rods; every other rod having opposite polarity, mlz is the mass to charge ratio of the ion traversing the multipole ion guide, is the frequency applied, Y is the zero-to-peak AC potential applied to the rods, every other rad being 180 degrees out of phase, and ra is the radius from the assembly centerline. When the multipole ion guide is operated in the AC-only mode, U is set equal to zero so an drops o~tt of the equation of motion.
~'he DC rod offset potential applied equally to all rods only effects the ion trajectories entering and leaving the multipole ion guide 40. The offset potential should not effect the stability of the ion trajectories once the ions pass into the ion guide and are trapped within the rods other than to i~luence their initial ezttrance trajectory and velocity. For the configuration shown in 1~igure Z, the background ga.s pressure inside the rod assembly varies along the multipole ion guide length and will effect the ion trajectories through the ion guide, To theoretically model the effect of the background neutral gas collisions oz~ the ion trajectory through a multipole ion guide, the cross section of the ions must be known, The collisional cross sections of ions generated by API sources, in particular the cross sections of multiply charged ions produced by electrospray ion sources, aiCe not always known.
Consequently, for multipole ion guide configurations described by the invention, values of a" and q" for which efficient iort transmission through the multipole lens is achieved were experimentally determined over a range of ion tnlz and background pressure combinations.
With a" = 0, the rod AC voltages were tamped for different radio frequency (RF) values using the multipole ion guide configuration diagrammed in Figure 2, to map the regions of stable q" for all m/z falling within the range of the quadrupole mass spectrometer. The background pressure gradient was held constant for each set of ion transmission tests to establish the values of q" where stable and efficient ion trajectories through the two vacuum stage multxpole ion guide 40 could be achieved. The number of ion to neutral gas collisions that occur as an ion transverses the rod length is a function of the background pxessuie as well a5 the rod length. The longer the rods, the more collisions which occur for an ion traversing the rods in a given background pressure. The multipole ion guide assembly 40 was constructed with an effective inner diameter smaller than 2_5 millimeters to minimize the neutral gas conduction between vacuum stages 41 and 42. The rod length in vacuum stage 41 was 2.9 cm and the rod length in stage 42 was 3.0 cm. For this multipole ion guide configuration and background pressure gradient tested, the AC voltage applied was kept below the point where electrical breakdown occurred between the rods. To determine which values of q" allow a stable trajectory for an ion with a given m/z and charge state, the multipole RF
amplitude was tamped for set frequencies ranging from 1 to 10 MEN, ZD
Are example test series is given in Figure 3a, 3b and 3c taken with following background pressures: pumping stage 53 was 2 too, pumping stage 41, 150 millitorx', pumping stage 42, 4 x 1,0'~ tort and pumping stage S4 was 6 x 10'6 tozx'. Fot the data taken in Figure 3a, the quetdrupole mass filter was scanned from m/z 109.6 to 110_6. The ion signal was measured at each 1 MI~z step of the kF frequency varying the RF amplitude to ftnd the ~onaximum signal.
At each RF frequency the RF amplitude was camped from minimum to maximuiu aad then tamped back tn its minimum value. At point 61 inn k'igure 3a the iwo vacuum stage multipole ion guide is being operated in the AG-only mode with its RF frequency set at 3 MHz and the RF amplitude set low, As the 1tF amplitude is camped to its maximum value at 62, the ion transmission efficiency for milz 110 reaches its maximum at 63 far this frequency. From 62 the amplitude is camped down to its original low value at 64 where little or no ion transnc~ission is observed. The signal maximum observed at 65 has roughly the same RF amplitude as at 63 as expected since the same value of q3 occurs at points 63 and 65. At att IZF frequency of 5 MHz, the RF amplitude -is tamped from a mi~ai,mum value at 6b to a maxinnuzn at 67 returning to ~ minimum at 68. The relatively flat top shape of tl~e ion signal which occurs between 78 and 67 indicates that very efFcient ion transmission at mlz 110 is occurring over a range of 1tF
amplitude or q3. Figure 3h shows the ion transmission e~ciency for m/z 872 generated simultaneously with the data shown in Figures 3a and 3c. The quadrupole mass filter was scanned from m/z 871.7 to 872.7 while applying the same values of RF frequency az~d amplitude as were run for m/z 110 in Figure 3a. The RF amplitude was set at 1 MHz witlu a low amplitude at 69, As the RF amplitude was increased from a miniznunca at 69 to a ma~tinfiuzn at 71, the maximum ion transmission occurred at 70. As expected, the maximum ion transmission occurs at the . same g3 value when ranxping the RF
amplitude from its maximum value at 71 back to its r~aauimum at 72. When zI
the frequency is increased to 3 MHz and the RF amplitude tamped front a minimum at 73 to a maxinnum at 74 back to a mizumum at 75, efficient ion transmission is achieved over a wide range of Itl~ amplitude or q~. Figure 3c shows the ion transmission efficiency for m/z 1743 (scanned firom 1742.5 to 1743.5) over the same ItF frequency and amplitude ranges as were used for mlz 110 shown in Figure 3a, Figure 3 illustrates that for a given background pressure gradient, varying orders of trtagnitude over the multipole iozt guide length, efficient ion transmission through the ion guide operated in the AC-only mode can be achieved for a broad range of m/z values, For example, if the maximum e~ciertcy in ion transmission were desired over the entire range of mJz tested in Figure 3 then the RF frequency would be set at 4 MHz and run with an RF amplitude that could fall roughly ax the qj value indicated at point 76. For this fluted value of q3 and background pressures at which the transmission efficiencies were measured, m/z va]ues frottu less than 1 x0 to over 1743 would be efficiently transmitted through the multipole ion guide. Figure 4 is a mass spectrum of Glucagon taken with the ion guide q3.value set at the point indicated by 76 in figure 3. A solution of 2 pieomole/ I of Glucagon in 1;1 methanol;water was Electrosprayed using continuous infusion sample introduction in art APIIMS instrument as configured in fiigure 2 and the quadrupole mass spectrometer was scanmed from 20 to 1900 xz~Jz, The (M+4H)''4, (M+3~)+' aad (IvI+ZI~);~ Glucagon peaks are indicated by 80, 81 and 82 respectively. The use of a multiple pumping stage nxultipole ion guide to transmit and focus ions exiting from a free jet expansiozt into a mass analyzer allows flexibility in configuring an Af1/MS instrument vacuum and ion optics system without eomproxnising sensitivity. Smaller utultiple pumping stage API/NiS instruments can be configured with vacuum puzttps chosen to minimize instrument cost without compromising performance. Multiple pumping stage multipole ion guides caa be configured and operated to allow e~cie~nt ion transmission and 2i focusing over a wide rage of pressure gradients. For the configuration illustrated in Figure 2, the background pxessure in the second vacuum stage 12 was set at different values covering a range greatex than 200 millitorr to less than a few millitorr with little change in ion transmission efficiency.
pue to this wide range of operating pressure possible with taxis invention, different embodiments of multipole ion guides described herein care be configured for use with a number of mass analyzer types which may require diffexeut operating pressure regimes. For example a quadrupole mass analyzer can operate efficiently at a vacuum pressure of 1 x 105 ton or below whereas a TOF analyzer requires background pressures in the low 10'' tort raztge or lower to avoid significant numbers of collisions between ions arad background gas during the ion flight time, A multiple vacuum pumping stage API/MS instrument with wide pressure range single or a multiple puznpiztg stage multipole ion guide can be oonFtgured to maximize ion transmission aztd focusing yet m~tnimize pumping cost.
Figure 3 illustrates That the cr" and q" values can be set so tb,at a low or a high m/z cutoff in ion transmission occurs. For example with a" - 0 if the RF
frequency were set at 3 MHz and the 1~F amplitude operated anywhere from poixit 79 to 62 then ions with m/x 1 XO or lower would not be transmitted through the multipole ion guide to the mass analyzer. Similarly, if the RF
frequency were operated at 7 Ml~z with the RF amplitude set at the value indicated by 77 then a high rn/z cutoff in iota tzansmission through the ion guide to the mass analyzer would occur. Figure Sa and Sb illustrate operation of the multipole ion guide 40 with the q~ value set for passing a broad range of m/z in Figure Sa and the q" value set at a point where a low ict/z transmission cutoff occurs in Figure Sb, Figure Sa is a mass sgectzutxt taken from electrospraying a solution of ~2 picomole/ 1 of Arginine in 1:1 txtethanol:water using continuous' iid'usion with the multipole ion guide 40 q3 value set to transmit a wide range of m/z values. The catiort impurities of sodium 85 (m/z 23) and potassium 86 (rrt/z 39) present in solution appear in the mass spectrum as well as the protonated methanol rxaonomer 87 (m/z 33) and dimer 88 (m/z 65) end the sample Arginine protonated peak 90 at mix 175. l figure Sb shows a rrtass spectrum taken with the same solution being Electrosprayed under identical spxay conditions but with the hexapole ion guide q, value was set so that a low m/z cutoff occurs, Ion transmission below 100 to 120 nn/z has been effectively cut off without reduciztg the ion transmission efficiency of Arginine 91 or higher m/z values, Another eple of this is illustrated in Figure 6a and bb where a 2 picomole/ 1 sample of Gramicidin S in 1:1 methanol:water was Electrasprayed with continuous infusion using the API/MS configuration illustrated in Figxre 2.
In Figure 6a the hexapole 40 g,~ value is set to transmit a wide mla range and an impurity potassium peak 92 and the protonated doubly charged Gramicidin S peak 93 (M+2I-~+z are observed in the mass spectrum, Figure tSb is a mass spectrum of the same Grz'amicidin S solution Electrasprayed using identical conditions as in Figure 6a but with the hexapole 40 q3 value is set so that a low tnlz cutoff occurs. The potassium iozts are no longer transmitted to the mass analyzer but the ion transxnission efficiency of the doubly charged Gramicidin S ions as sb,own by peak 94, is still retained. A q" value can also be selected to cause a high rnlz cutoff as illustrated in figure 7a and 7b where a ~lx~.i~tture of Arginine, Leucine Enkephalin and G~ramicidiz~ S, 2 picom,ole/ul each in 1:1 methsnol:water was Electrosprayed using the APX/MS
configuration shown in Figure 2. Figure 7a is a mass spectrum taken where tha multipole ion guide 40 q~ value was set to transmit a wide range of rn/z values. The Arginiae (M+H)+ peak 95, heucine Encephalon (M+H)~ peak 96 and doubly charged Gramicidin S (M+2H)+2 peak 97 are present in the mass spectrum as well as the Iower mlz ion peaks 98. Figure 3b is a txiass spectrum taken where tlae same solution is Electrosprayed using identical spray conditions except that the ion guide 40 a" and q3 value has been set so that the lower m/z ions are transmitted as indicated by peaks 99 but the higher mJz ions are not transmitted through the multipole ion guide 40.
p valuable feature of multipole ion guides when operated in higher b$ckground pressures is that ions traversing the length of the ion guide experience a number of cohisions with the background gas resulting iii the cooling of the ion kinetic energy. As the ions enter the n~ultipole ion guide and are transmitted through it, the 1tF or combined RF-DC held effectively traps the ions from dispersing in the radial direction due to collisions with the background gas yet permits txtovement of ions in the axial direction driven in part by the gas dynamics, The cooling of ion kinetic energy due to collisions with the background gas results in a narrowing of the ion energy spread for those ions which exit the multipole rods. The number of collisions an iott experiences as it traverses the length of the ion guide is a function of the rod length, the background pressure inside the rod assembly and its trajectory as dx;ven by the varying electric field_ When the background pressure along a portion of the ion guide assembly is high enough resulting in marry iort to neutra'1 molecule collisions, the ion guide DC offset potential, can be used to set the mean energy of ions which exit the ion guide, Also, operating a multipole ion guide with a portion of its Ieztgth in a higher piessuxe region where ion collisional cooling occurs, the resulting narrow energy spread of the ions transmitted can be maintained independent of changes in the mean ion energy when the iozt guide DC offset potential is adjusted, It was found with the apparatus diagrammed in Figure 2 that with 150 irtillitorr background pressure maintained in the second vacuum stage 12, the skimmer 47 potential could be adjusted over a range of voltage relative to the DC
offset potential of the ion guide 40 with little change observed to the mean ion energy or the energy spread for ions emerging fxozn the iort guide.
Although the electric fields applied to the electrodes of ion guide 40 are the dominant force effecting the iozr motion along anost of the ion guide length, the gas dynamics occurring within tl;Ae ion guide over a portion of its length play a significant role in establishing the ion energy and eztergy spread. It is likely that the higher pressure near the ion guide 40 ezttrance helps tp increase the trapping efF~ciency of ions entering the ion guide, To illustrate the effects of gas dynamics within the ion guide illustrated in Figure 2, the energy spread of a doubly charged Gnramicidin S (M+2~''~ ion (nnlz 57I) was measured by rarnping the voltage of lens 53 in Figure 2 while monitoring the mass spectrometer ion signal. This technique will not give a precise profile of ion energy ,because lens 53 a a focusing element as well as having the ability to apply stopping potentials. However, even; though the focusixag characteristics will change as the voltage of 53 is camped, the boundaries of ion energy for a given mlz can be attained, Using the multipole ion guide configuration of Figure 2 and maintaining background pressure in vacuum stage 53 at 2 torr, vacuum stage 4I at 150 millitorr, vacuum stage 42 at 4 x 10'' torn and vacuum stage 54 at 6 x 10-6 tour, the ion energy was changed by adjusting the DC offset potential of the hexapole relative to tire quadrupole entrance aperture 47 ground potential. Figures 8 a, b and c show the ion signal of the Gramicidin S protonated doubly charged peals (M+2H)+= for three different hexapole ion guide 40 DC offset potentials. In figure 8a the hexapole ion guide 40 was operated in the AC
only mode with the DC offset potential set at 0,1 volt relative to the quadrupole entrance aperture 47. Figure 8a shows the ion signal level 140 at m/z 571.6 for three consecutive voltage ramps of lens 53 from 2 to 8.2 volts.
Over ninety percent of the mlz 571.6 ions fall within a one volt window of ion energy. Figure 8b shows the ion signal 101 at m/z 571.6 fox three consecutive voltage ramps of lens 53 from 19 to 21.2 volts with the hexapole ion wide 40 DC offset potential set at 15.3 volts. Ninety percent of the 571.6 m/z ions detected have an energy that falls within a otte volt window, SiW iIarly, Figure 8c shows the ion signal 102 at m/z 571,6 for tlu'ee consecutive voltage ramps of lens 53 froth Z9 to 35 volts with the hexapole ion guide 40 DC offset potential set at 25.1 volts. Once again, over ninety percent of the mlz 5T 1,6 ions exiting the hexapale ion guide 40 are within a volt energy window. The mean ion energy ranges from roughly 3 to 5.2 volts higher than fife DC offset potential set on the hexapole ion, guide 40 in Figures 8 a, b and c, Ion acceleration driven by the expanding gas in the free jet occurring in vacuum stage 51 may account far 2,6 to 3 volts of this added ion energy for Gramicidin S ia~. It is not yet certain where the one to two volts of energy over 3 volts is added as the multipole ion guide DC offset potential is raised. The efficient transport of ions with low energy spzead combined with the ability to control the average ion energy for a given mlz by adjusting the multipole ion guide 40 DC offset potential, allows higher sensitivity to be achieved at higher resolution fox many mass analyzer types, An API/MS system which incorporates a multipole ion guide with a portion of its length operating in a vacuum pzessure which is high enough to cause eollisional cooling as ions traverse the rod length allows three signif cant performance features, The first is that the ion guide operated in the presence of sufficient background collisions can reduce the ion en~exgy spread without reducing tan transmission eflicieztcy when run with the proper values of a"
and q" set. Second, the mean ion energy for a given mlz cant be adjusted by changing the DC offset potential of the multipole ion guide without causing significant changes in ion energy spread. Third, the ion energy cart be adjusted by changing the ion guide DC offset potential without reducing tlxe ion transmission c~ciency through the multipoIe ion guide. An example to lhustrate these three features is given in Figuo~e 9 which shows a mass spectrum 103 of a daubly charged protonated Qramieidin S (1vI+2I~'~s peak with partially resolved isotope peaks. The spectrum was taken by electraspraying a 2 picomole/ul Gramicidin S sample in a 1:1 metbar~ol: water solution using ~n API quadrupole rriass spectrometer system as configured in Figure 2. The DC offset potential of hexapole 40 was set to 0.1 volts relative to the ground potential duadrupole entrance aperture 47, At lower ion energies, transmission 1055e5 cad OCCLV between the multipole ion guide exit 52 and the quadxupole mass filter 57 depending on the focusing and transfer characteristics of static voltage lenses 53 snd 47 in the presence of the multipole ion guide 40 and the quadzupole mass filter 57 fringing f elds, The performance tradeoffs between ion extergy, resolution axed signal level for the quadrupole mass filter 57 used, favored lower energy ions when scanaing with higher resolution settings. Using a static voltage lens system as illustrated i~ Figure 1 the resolution and sensitivities shown in Figure 9 could not be achieved, The use of a multipole ion guide operated with the appropriate a~ and g" setting izt a region where background pressures are high tnough to cause collisions! cooling of ions as they traverse the length of the ion guide improves APIIMS system performance when compared with static lens co~gurations.
The performance capabilities of a multipole ion guide operated in a background pressure region where ion kinetic energy cooling occurs cart be used tv improve the performance of different mass spectrometer types. The advantages of improved ion transmission efficiencies when using multiple vacuum pumping stage multipole ion guides in conjunction, with quadzupole mass analyzers was illustrated with examples given above, The ability to set the mean ion energy by adjusting the multipole DC offset potential without changing the narrow energy spread per m/z can be used to improve the resolution and sensitivity of APIIMS instruments where the mass analyzer may be a quadrupole, magnetic sector, TOF, ion trap or an FT-ICR mass spectrometer. Higher API/MS system sensitivities and resolutions can, be achieved and pumping costs minimized when multipole ion guides which extend through two ox more vacuum pumping stages are used in the initial vacuum pumping stages before the mass analyzer. The ability to operate a multipole ion guide in a mode where a cutoff in ion transmission for a given mlz range is set may not offer an operational advantage when applied with scanning mass analyzers such as magnetic sector or quadrupole mass filters, These scanning mass analyzer types transmit ions only in a narrow range of mlz at any given time to the detector. However, for mass attalyzers which employ trappi~ag andlor non scanning techniques such as TOF, ion traps and FT-ICR, the ability of the xnultipole ion guides to limit the range of m/z values transmitted into the mass analyzer can euhaace system performance.
Ffgut'e 10 is a diagram of a four vacuum pumping stage orthogonal pt~lsxr~g A~PI/MS system with a xeflectron Time-Of Flight mass analyzer. For illustration purposes, an electrospray ion source is shown as the APT source although this could alternatively be an APCI ox an ICP source as well.
Sample bearing liquid is introduced through the electrospray needle 110 and i~ Eleetrosprayed or nebulizrstior~ assisted Electrosprayed into chamber 111 as il exits the needle at 112, The charged droplets produced, evaporate and desorb gas phase ions both in chamber I I1 axad as they are swept into vacuum through the annulus iz~ capillary 113. A portion of the ions that enter the first vacuum stage 133 through the capillary exit 114 are focused through tie orifice 136 in skimmer I 16 with tlae help of lens 115 and the potential set dt~ the capillary exit 114. Ions passing through sltiznmer orifice 13b enter the timltipole ion guide 118. The ion guide 11$ begins in vacuum pumping stage x 17 and extends unbroken into vacuum stage I 19. If the multipole. ion guide AC and DC voltages are set to pass ions falling within a range of m/z then ions within that range which enter the multipole ion guide will exit at 121 ~d are focused with exit lens I20 through the TOF analyzer entrance orifice I22. This primary ion beam 134 passes betvv~eer~ electrostatic lenses 123 arid 124 located in the fourth pumping stage 1ZG. The relative voltages on lenses 123, 124 and 125 are pulsed so that a portion of the ion beam 134 falling in ~etween lenses X23 sad 124 is ejected as a packet through grid lens 125 and I

accelerated down flight tube 127. The ions are steered by x and y lens sets diagrammatically illustrated by 12$ as they continue their movement down flight tube 127. In the conf guration shown, the ion packet is reflected through a reflectron or ion mirror 130 and detected at detector 131. As a pulsed ion packet proceeds down flight tube 127, ions with different mlz separate in space due to their velocity differences and arrive at the detector at different times. The use of oztixogonal pulsing in an API/TOF system helps to reduce the ion energy spread of the initial ion packet allowing higher resolution and sensitivity to be achieved.
For a given primary ion beam current passing through the mass analyzer aperture 122, the lower the ion energy, the more ions that will be present it1 the pulsing region per pulse. "his has a direct impact on the ion signal response that can be achieved per pulse. Also, the Iower the primary ion beam electmstati~c energy, the less ion density versus m/z discrimination that ~.vill occur in pulsing region 135. This discrimination occurs because tlae lower m/z ions accelerated electrostatically will move faster than the higher m/x ions and consequently will have less relative density for a similar ion current per tnJz in the pulsing region. A distinction is made here between ions accelerated electrostatically and those accelerated due to gas dynamics in the free jet. Although some slippage occurs for higher molecular rrtasses, ions accelerated solely by the neutral gas e~cp$ndin$ into vacuum in a free jet form an ion beam that is closer to being mono-velocity rather than mono-energetic. Electrostatic acceleration in the absence of collisions with baclGgound gas will cxexte an ion beam that is closer to bezz~g mono-energetic. A mono-velocity beam entering pulsing region 135 will reduce the differences in ion density versus mlz for a given ion flux and ben~ce allow ' ger~exation of a tmass spectrum whose relative peak heights axe more representative of the relative mlz intensities in the original ion beam 134.
'phe tran,slational energy of ions its the primary ion beam 134 will be the sum of the energy imparted by the e~pandiz~g g$s and by electrostatic acceleration.
Multipole ion guide 118, a portion of which is operated in a higher pressure vacuum region, can deliver an ion beach having low translational energy through the mass analyzer orifice 122 with minimal beam divergence. When static lens systems are used, lowering of the ion beam energy generally results in increased beam divergence. Heazn divergence will not only reduce the ion beam intensity entering aperture 122 but will also increase the beam cross sectional area in pulsing region 135. Primary inn beam divergence can result in reduced resolution in an orthogonal pulsed TOF geometry. Use of the multipole ion guide l I8 to aid in delivering ions to the pulsing region can reduce the degree of ion beam divergence for lower ion beam energies. The net result is improved sensitivity and resolution.
The effective inner diameter of multipole ion guide 118 is reduced to xni~nirnize the neutral gas conduction between vacuum pumping stages 117 and 119 wj.thout compromising ion transmission efficiency. The effective inner diameter for multipoIe ion guide 118 is typically 2.5 millimeters or less.
The ion guide geometry itself places an upper limit on the cross section of the ion beam exiting at 121. By lirraiting the ion beam diameter exiting multipole ion guide 118 to less than 2 mm, aperture 122 can be reduced to 2 txun with little or no loss ion transmission efficiency into pulsing region I3S.
The smaller the aperture 122 size the less neutral gas that will pass into vacuum pumpizrg stage 128, reducing the vacuum pumping speed requirements and lowez~g instrument cost. The smaller the primary ion beam 134 which enters pulsing region 124, the less spatial spreading which occurs before the ions are pulsed out of region 135 and into flight tube 127, With orthogonal pulsing, reducing the ion beam 134 width can reduce the pulsed ion pacl~et width or spatial and energy spread, potentially resulting in increased TOf sensitivity and resolution petfortnance.

A marrow ion energy spread is desirable iz~ orthogonal pulsing TOF because the orthogonal component of ion energy which is the initial ion beam energy, translates into sideways movement of ions as they traverse ttae flight tube, The lower the energy spread in the initial ion beam the tighter the initial m/z ion packet remains in the radial direction as it travels through flight tube resulting in more ions focused onto the surface of detector 131, As shown in Figure 8, operation of a multipole ion guide in a vacuum pressure regime where ion kipetic energy cooling occurs results in narrowing of the ion energy spread and the ability , to lower iozt energy without reducing the ion transmission efficiency or increasing the ion energy spread, The ability to Iower ion energy while maintaining a low ion ezrergy spread can help to improve the sensitivity and increase the duty cycle of a TOF mass analyzer.
Ions of a given m/z and energy will take time to refill the gap between lenses 123 and 124 after a pulse ha_s occurred. If the length of the gap is roughly 2 cm then an ion at m/z 1000 with 20 volts of energy will take 10.2 sec to travel 2 cm and fill the pulsing space, The same ion at 3 volts of energy will take 26.3 sec to travel 2 cm arid fill the pulsing region. Those ions which are not pulsed into the flight tube are lost as they impact the walls of pulsing regiorx 134 and are neutralized: If the ion packets are pulsed at a rate of 14,000 times per second, that is once every 100 sec, then pulsing a 3 volt primary ion beam 134 will ixz~prove the duty cycle and conseqrendy the seztsitivity by a factor of 2.6 when compared with pulsing a primary ion beam 134 having 20 volts of translational energy_ The ability of a multipole ion guide to deliver ion beam 135 with a small cross sectiozt and a reduced mean energy, significantly improves performance of an API/TOF system over that which can be achieved using a static voltage lens system, The ability of the multipole ion guide to selectively, transmit a range of m/z va]ues while Eutting off the transmission o~ mla outside that range can be used to increase the duty cycle an,d detector sensitivity in an API/TOF
system. The duty cycle can be izacreased in TOF by reducing the range of ion m/2 that enters pulsing region 135, Recalling figures 5, 6 and 7, the a"
and q" values of a multipole ion guide can be set so that the ion guide behaves as a low pass ox a high pass filter with m/z transmission cutoff points. If a J7C potential is applied to the poles where each adjacent pole has opposite DC polarity, the a" and q" values can be selected so that the raiultipole ioa guide will pass a narrower xaz~ge of m/z. Quadrupoles aze commonly used in this mode as mass filters in vacuum pressure regimes that ar'e maintained below 2 x 10-5 torr where the effects due to ion collisions with the background gas aze negligible. When +~/- DC is imposed on the multipole rods with considerable background pressure present, the transmission characteristics of each type multipole ion guide or mass filter assembly nrlust t~;sted and qualified. Ion transnussion maps of a" and q" may not be the same for multipole ion guides with different numbers of poles and operated in different backgrouztd pressures. One variable which effects duty cycle in a TOF instrument is the repetition rate at which ions are pulsed in the flight W be, accelerated and detected. Assuming that the pulsing region 135 can refill between pulses, that is the primary ion beam 134 energy is set to satisfy $us criteria, the pulsing repetition rate will be limited by the fastest flight time of the lowest m/z ion and the slowest flight time of the highest m/z ion in consecutive ion packets traveling through flight tube 127 to the detector.
Any 'overlap of io»s from one pulsed packet to the next will increase the difficulty in iu~terpreting the resulting mass spectrum. if ions of lower or higher m/z were not of interest in a given analysis, those ions could be preventing from enteriztg the pulsing region by selecting an appropriate a"
and q" value for the multipole rod 118 operation. By reducing the arrival time spread of an ion packet as it travels down the flight tube, the time in between pulses can be reduced resultiang in an increase in duty cycle, Consider an example where an APIIMS system as diagrammed in Figure 10 has an effective ion flight length of Z.5 meters an,d a flight tube ion acceleration energy of 1500 electron volts (ev). 'fhe larger tire difl'erence in arrival times at the TOF detector between Close ion m/z values, the higher the resolution which is theoretically achievable. However, for continuous ion beam API sources, increasing resolution by increasing the arrival time, spread of ion packets may reduce duty cycle. relative flight times in a 2.5 meter TOF tube with an ion accelerating energy of 1500 ev would be as follows for different values of mlz;
mlz Flight time ( sec) 1 4.6 19 20.3 100 46.5 500 103.9 1000 146.

2000 207.8 3000 254.5 5000 328.6 10000 464.7 Subtracting the slowest from the most rapid flight time of ions present in the pulsed packet will determine the minimum time required in between con,seeutive pulses to avoid low m/z ions of the trailing pulse catching up with high m/z ions of the leading pulse. xf m/z ions ranging from pxotonated water (m/z 19) to m/z 3000 are present in the pulse iox, packets, then a delay of 255 sec must be maintained between consecutive pulses allowing alrproximately 3,921 pulses pez~ second, A primary ion beam 134 with sons of tn/z of 3000 and lower end with 3 volts of translational energy will fill the 2 em pulsing gap 135 length in less tlxan 45 sec. The longer the delay .

between pulsing of ions into the flight tube, the lower the duty cycle resulting iz~ lower sensitivity for a given primary ion beam intensity, if the ions of interost for a given analysis fell in a narrower m/x window, say below m/z 1000 then the multipole ion guide a" sad g" values could be set to pass only ions below mlz 1000. The minimum time delay between pulses would be xeduced to I47 sec effectively increasing the duty cycle and potentially sensitivity by a factor of 1.7. Conversely, if the mass range of interest fell above m/z 500 and the m/z values present in the primary ion beam were below 2000 m/z then the rnultipole ion guide 118 operating a" az~d gn values could be set to reject ions below 500 m/z. The ion packet pulse frequency could be set to over 9500 pulses per second increasing duty foX all m/z values transmitted into pulsing region 135.
Layered Multichannel Plate (MCp) electron multipliers are often used for detectors in TOF mass spectrometry. The individual channel recovery time of an MCP channel after an ion hits and causes an electron cascade may be as long as 1 millisecond. If an ion hits the channel before it has recovered thezt little ox no electron cascade will occur and the ion will remain undetected. Lower m/z ions which arrive at the detector first for a given pulsed ion packet could deaden channels for heavier m/z ions which follow.
Also if the packet pulse rate exceeds 1000 hez~tz, that is the time between pulses is shortex than the IvICP cl~azu~,el recovery time, this could result in reduction in signal intensity as ions arriving at the detector yield reduced secondary electron cascade intensity because ions from preceding pulses have deadened a number of channels. If the ions of interest for a given analysis fall within a lixt~ited xn/z range, detector response can be increased for ions of interest by preventing unw~.ted nn/z values from reaching the detector. The ' multipole ion guide I 18 nn/z transmission window can be selected to minimize the number of unwanted m/z values from entering the pulsing region 135, eairaainatir~g those m/z values from reaching the detector.

Selectively preventing Ions from reaching the detector has also been accomplished by deflecting a portion of an ion packet as it traverses the TOF
tube before it reaches the detector. Ion lenses used for deflecting ions are diagratxunatically represented by 132 in figure 10. The use of multipole lens to limit tn/z values from entering the TOF pulsing region is a complimentary technique to using deflectors in the flight tube. Deflecting lenses, however, well not aid increasing duty cycle unless they are employed very early in the ion flight path, a region where m/z separation may be poor. A linear pulsed API/MS system as reported by Boyle, UVhitehouse and Ferro (Rapid Communications in Mass Spectrozn. Vol, 5, 400-405, 1991) can have a similar increase in se~asitivity and duty cycle by incorporation of a multipole ion guide into tk~e upstream vacuum stages as is achieved in orthogonal pulsing TOF configurations.
'When APT sources are interfaced with iota traps and FT-ICR mass analyzers, the use of tnultipole ion guides in the vacuum transfer optics can be used to improve performance by increasing ion traztsmission efficiency into the mass analyzer trapping region, lower the ion energy spread and reducing space charge limits for desired m/z ranges by selectively transmitting limited m/z ranges. Also the ability to lower ion energy and energy spread over a range of m!z ions helps to increase the trapping efficiency in ion traps and FT-ICR
mass analyzers. One embodiment of the rraultiple pumpitrg stage multipole iori guide used in conjunction with ion trap mass analyzers can be accomplished by replacing the quadrupole mass analyzer shown in Figure 2 with an ion trap, Another embodiment of the invention is illustrated in Figure 11. Figure 11 diagrams a three vacuum pumping stage API/ion trap systcrn, where a multipole ion guide begins in vacuum pumping stage 148 and e;x'tends continuously through the three vacuum pumping stages. An electrospray or nebulizer assisted electrospray ion source is shown, interfaced to ion trap mass spectrometer 154. Sample bearing liquid is introduced into the electrospray needle entrance 140 and is Electrosprayed or nebulizer assisted Electrosprayed as it emerges fzom the electrospray needle tip 141.
The charged liquid droplets produced in the electrospray chamber 142 drift toward the capillary entrance 144 against a flow of countercurrent drying gas 164, Ions are produced from the evaporating charged droplets and are swept into vacuum through capillary 145. This capillary may be heated by cap111ary heater 146 which aids in heating the gas expanding through the capillary into vacuum. Ions exiting the capillary at 147 are accelerated into the first vacuum pumping stage 148 by the neutral gas free jet expansion. A large portiozt of ions exiting the capillary enter the multipole ion guide 165 and are effectively trapped and efficiently transported through its entire length, The ions exit multipole ion guide 165 in the third vacuum stage 151 and are focused into the ion trap 154 through the its endplate 155 by lens 162. By orienting the ion trap at an angle, ions can also enter the trap through the gap between the endcap and 1ZF electrode. The pressure in vacuum stage 148 can range from 0.1 to 2 tort depending on the capillary 145 iruzer diaxn,eter and IPn~gth, the vacuum pump size chosen and the temperature at which the capillary heater is run. The third pumping stage 151 is usually maintained at a pressure below 5 x 10'' tort to insure proper functioning of the electron multiplier detector 152, however, the internal trap pressure is often set higher than the background pressure in stage 151 by the addition of helium directly into trap 154. The pressure in purtaping stage 157 1s generally maintained at a pressure Less than 150 millitorr.
The multipole ion guide 165 has rods or poles 150 which, begin in pumping stage 148, continue unbroken through pumping stage 157 and extend into pumping stage 151. Insulators and mounting brackets 156 and 158 serve the dual purpose of supporting the multipole rod assembly and partitioning the vacuum chambers to rn.iniznize the flow of background gas into downstream pumpizig stages, Figure 12 illustrated a cross section of a hexapole assembly taken at insulator 156. The six rods 160 are held in an equally spaced position and equal radial distance from the centerline by attachment to insulator 156. The insulator is configured to minimize the effective cross sectional area of the internal opening without distorting the electrostatic field produced by the hexapole rods during operation inside multipole rod assembly cross section area 161. Rod diameters as small as O.S mm have been constructed with an inner rod spacing 166 of 2 mnn to minimize neutral gas conductance into downstream pumping stages aid reduce the size and Cost of vacuum pumps required. Increasing the insulator 156 and 158 lengths along the axis also helps to reduce the neutral gas conductance from one vacuum pumping stage to the next. The smaller the ian guide assembly internal cross section area 161 with proportionally small rod 160 diameters, the smaller the ion beam cross section which exits the multipole ion guide.
The smaller the ion beam cross section which is transmitted through a multipole ion guide 165 and exit lens 162, the smaller the effective aperture' size which is required ins ion trap end plate 155.
The multipole ion guide 16S can efficiently transport ions through gradient in baclGground gas pressure. As was shown in Figures 8a, b and c, the ion energy spread is reduced due to ion collisional cooling with the background gas. ' Higher trapping efficiency can be achieved with ions entering ion trap 154 when the ions have a narrow energy spread and lower average energy.
Increased trapping efficiencies result in higher sensitivity for a given eon current entering trap 154. The ability to selectivity cutoff a range of m/z transmission through multipole ion guide 16S can be used to increase sensitivity and signal dynamic range itt ion trap mass spectrometers. Ion traps must first trap ions before conducting a miss analysis on the packet of trapped ions, The trap can only hold a limited ztumber of ions before it suffers from space charge effects which can shift measured m/z values and deteriorate resolution, For a given analysis, the rnultipole ion guide a" and q"
value cats be set to reduce the m/z range of ions which are transmitted to ion trap 154 through exit lens 162 and ion trap endplate 155. This extends the dynamic range signal response for the mlz values o~ Interest by reducing the effects of space charging from m/z values which are not of interest for a given analysis. For example, the contamination 85, 86 and solvent related pealCS 87, 88 observed in the spectrum of Figure Sa would contribute to falling the trap with charge and reduce the signal intensity range over which the Arginine peak 90 could be observed in the f on trap because the lower mlz peaks would be largely responsible for the space charge limits being reached in the ion trap. If the multipole ion guide a" at~d q" value were set for a tow zn/z cutoff as shown in the spectrum of figure Sb then the Arginine peak 91 would be the primary source of ions entering the trap and consequently the signal to noise observed would have a higher dynamic range before the effects of space charging would be observed. Increased dynamic range within a spectrum is important for trace analyses az~d analysis where accurate relative peak heights are needed to determine relative coztcentrations in solution, FT-ICR mass spectrometers also trap ions and conduct mass analysis with packets of sons. Similar to ion traps, improvements in performatace with an A~Px/FT-ICR MS instrument can be achieved by using a multipole ion guide operated in vacuum pressure were ion kinetic energy cooling occurs reducing the ion energy spread for a given m/z. Effects due to space charge limits in the FT-ICIt MS trapping cell can be reduced in a similar manner as described for ion traps above effectively increasing the dynamic range of the FT-ICR
MS for m/z values of interest in a given analysis. The smaller effective inner diameter of these xraultipole ion guides produces a small ion bexxn cross section allowing a reduction in the aperhue sizes leading,to the FT-ICR mass analyzer witkxout significantly reducing ion transmission through the smaller orifices, Various co~guration5 of hybrid APItmass spectrometers have been reported whose performance would be enhanced by the incorporation of a multipole ion guide in the vacuum ion transport region. Chien, Michael and Ludman (Anal. Chem., vol. 65, 1916-1924, 1993) have used an ion trap to trap ions entering from an API source and pulse than into a TOF mass spectrometer flight tube, A multipole ion guide could be effectively employed in the upstream vacuum stages to transmit ions from the higher pressure vacuum regions into the ion trap of this Al?I/ion trap/I"OF instrument.
Each mass spectrometer type has its own ion energy, entrance optics and vacuum requirements. The configuration of multipole ion guides, particularly those that extend through two or more vacuum pumping stages can be geometrically and operationally tailored to maximize the performance of the instrument in which they are incorporated. However, for some instrument geonnetries single pumping stage multipole ion guides may be used. Two variations for configuring multipole ion guides in APIlMS TOF and ion trap systems are shown in Figures 13 and 14. Figure 13 is a diagram representation of a 3 vacuum stage API/ion trap mass spectrometer system where a multipole ion guide 170 is located in vacuum pumping stage 172.
Ions passing from pumping stage 171 through skimmer orifice 176 are ttapped from moving to far of~~ axis in the radial direction and transmitted through ion guide 170. The ions exiting ion guide 170 are focused by exit lens 175 into ion trap 177 through endplate I74, The ion trap endplate aperture 17$, also serves as the orifice into the third vacuum pumping stage 173. Ions can be injected into an ion trap through different gaps or apertures in the ion tzap electrodes, however, this configuration is shown as one embodiment. The vacuum pressure in vacuum stage 1?2 and the multipole ion guide 170 length cart be configured. to cause sufficient ion collisional 4~
cooling with the baclGground neutral gas resulting in a narrowing of ioz~
energy spread for a given mlz, Use of a single pumping stage multipole ion guide may not allow the optimal tradeoffs in performance increase and vacuum pumping cost reduction as is possible with a continuous multiple puznpi.>ag stage multipole ion guide but some performance advantages can be realized when compared to using a static voltage Lens configuration.
Another variation with the use of multipole ion guides is the incorporation of two or more ion guides in consecutive vacuum puaxping stages. This allows different aA and q~ values to be set per ion guide but increases system complexity and cost. Figure 14 is a diagram of a four vacuum stage API/TOF meiss spectrometer system with single vacuum pumping stage naultipole ion guides 180 arid 181 located in pumping stages 184 and 185 respectiyely_ Xons ins vacuum stage 183 pass through slcimatter 190 and- enter ion guide 180. The ions which are transported through vacuum stage 184 by ion guide 180 are focused through the aperture 194 by multipole 180 exit lens 187, The ions then entez the a second ion guide 181 in vacuum stage 185 and are focused by lens 188 through aperture 189 as they exit the multipole ion guide 181. Ions passi>ag though aperture 189 into vacuum stage 186 are pulsed orthogonally with lens set 191 into the TOF mass analyzer 192. The multipole fort guides can be operated with independent values of a~ and q"
may be set to optimize the TOF duty cycle and sensitivity. Similar to the continuous multiple pumping stage multipole ion guide configuration, the dual multipoIe ion guide configuration as diagrammed in figure 14 can be used reduce the ion energy spread and deliver low energy ions into the mass analyzer. However, with the dual multipole ion guide configuration, losses tn iort transmission efficiency may occur in the region of static voltage lenses 187 and 195 between the two multipole assemblies 1$0 and 181.

Claims

CLAIMS:

1. An apparatus for analyzing chemical species, comprising:
(a) an ion source for producing ions from a sample substance;
(b) a vacuum region, said vacuum region comprising at least one vacuum stage, each of said at least one vacuum stage having means for pumping away gas to produce a partial vacuum;
(c) a Time-of-Flight mass analyzer having a pulsing region and a detector, said Time-of-Flight mass analyzer being located in at least one of said at least one vacuum stage;
(d) at least one multipole ion guide located in said vacuum region; and (e) means for applying electrical voltages to said at least one multipole ion guide.

2. An apparatus according to claim 1, wherein said vacuum region comprises at least two vacuum stages, said vacuum stages being in communication with each other such that said ions can move through a sequence of said vacuum stages.

3. An apparatus according to claim 1 or 2, wherein the first of said at least one vacuum stage is in communication with said ion source such that said ions produced by said ion source can move from said ion source into said first of said at least one vacuum stage.

4. An apparatus according to claim 1, 2 or 3, wherein said Time-of-Flight mass analyzer further comprises a Time-of-Flight tube.

5. An apparatus according to claim 4, wherein said Time-of-Flight mass analyzer is configured for orthogonal pulsing of said ions from said pulsing region into said Time-of-Flight tube.

6. An apparatus according to claim 4, wherein said Time-of-Flight mass analyzer is configured for in-line pulsing of said ions from said pulsing region into said Time-of-Flight tube.

7. An apparatus according to claim 4, wherein said Time-of-Flight mass analyzer further comprises an ion trap for pulsing of said ions from said pulsing region into said Time-of-Flight tube.

8. An apparatus according to claim 1, 2, 3 or 4, wherein said ion source produces ions from solution and delivers said ions into said vacuum region through an orifice.

9. An apparatus according to claim 1, 2, 3 or 4, wherein said at least one multipole ion guide is a hexapole.

10. An apparatus according to claim 1, 2, 3 or 4, wherein said at least one multipole ion guide is a quadrupole.

11. An apparatus according to claim 1, 2, 3 or 4, wherein said at least one multipole ion guide has more than six poles.

12. An apparatus according to claim 1, 2, 3 or 4, wherein said means of applying electrical voltages to said at least one multipole ion guide includes the application of AC and DC
voltages to said at least one multipole ion guide.

13. An apparatus according to claim 12, wherein said AC and DC voltages and the AC frequency are adjustable.

14. An apparatus according to claim 12, wherein said AC
frequency is fixed, said AC voltage amplitude is adjustable and said DC voltages are adjustable.

15. An apparatus according to claim 13, wherein said AC

frequency and said AC and DC voltages are set to limit the range of mass-to-charge of said ions which can be transmitted through said at least one multipole ion guide.

16. An apparatus according to claim 14, wherein said AC
frequency is fixed and said AC voltage amplitude and said DC
voltages are adjusted to limit the range of mass-to-charge of ions which can be transmitted through said at least one multipole ion guide.

17. An apparatus according to claim 13 or 14, wherein said AC
and DC voltages are adjusted to increase the duty cycle of said Time-of-Flight mass analyzer.

18. An apparatus according to claim 13 or 14, wherein said AC
and DC voltages are adjusted to select the energy of said ions entering said pulsing region of said Time-of-Flight mass analyzer.

19. An apparatus according to claim 13 or 14, wherein said AC
and DC voltages are adjusted to decrease said detector dead time of said Time-of-Flight mass analyzer.

20. An apparatus according to claim 1, 2, 3 or 4, wherein at least one of said multipole ion guides is located in one of said vacuum stages such that it begins and ends in the same vacuum stage.

21. An apparatus according to claim 1, 2, 3 or 4, each of said multipole ion guides in each of said vacuum stages begins and ends within its respective vacuum stage.

22. An apparatus according to claim 1, 2, 3 or 4, wherein at least one of said multipole ion guides begins in one of said vacuum stages and extends into at least one subsequent vacuum stage.

23. An apparatus according to claim 1, 2, 3 or 4, wherein at least a portion of said at least one multipole ion guide is located in an area within said vacuum region where the background pressure is sufficiently high such that multiple collisions occur between ions and background gas in said area.

24. An apparatus according to claim 1, 2, 3 or 4, wherein the background pressure in at least one of said vacuum stages where a portion of said at least one multipole ion guide is located is sufficiently high to cause multiple collisions to occur between said ions and neutral background gas molecules within said portion of said multipole ion guide resulting in reduction of kinetic energy of said ions.

25. An apparatus according to claim 1, 2, 3 or 4, wherein at least one of said vacuum stages into which said multipole ion guide extends is maintained at a background pressure of at least 1 millitorr.

26. An apparatus according to claim 25, wherein said background pressure is at least 50 millitorr.

27. An apparatus according to claim 25, wherein said background pressure is at least 100 millitorr.

28. An apparatus according to claim 25, wherein said background pressure is at least 150 millitorr.

29. An apparatus according to claim 1, 2, 3 or 4, wherein each successive vacuum pumping stage in said sequence of said vacuum stages has a lower background pressure than the previous pumping stage.

30. An apparatus according to claim 1, 2, 3 or 4, wherein the radial distance from the inner surface of a pole of said at least one multipole ion guide to the centerline of said at least one multipole ion guide is not greater than 1.5 millimeters.

31. An apparatus according to claim 1, 2, 3 or 4, wherein the radial distance from the inner surface of a pole of said at least one multipole ion guide to the centerline of said at least one multipole ion guide is not greater than 1.0 millimeters.

32. An apparatus according to claim 1, 2, 3 or 4, wherein the radial distance from the inner surface of a pole of said at least one multipole ion guide to the centerline of said at least one multipole ion guide is not greater than 2.5 millimeters.

33. An apparatus according to claim 1, 2, 3 or 4, wherein said ion source operates substantially at atmospheric pressure.

34. An apparatus according to claim 1, 2, 3 or 4, wherein said ion source is an Electrospray ion source.

35. An apparatus according to claim 1, 2, 3 or 4, wherein said ion source is an Atmospheric Pressure Chemical Ionization source.

36. An apparatus according to claim 1, 2, 3 or 4, wherein said ion source is an Inductively Coupled Plasma ion source.

37. An apparatus according to claim 1, 2, 3 or 4, wherein said ion source is an Electrospray ion source with pneumatic nebulization assist.

38. A method of analyzing chemical species, comprising:
(a) utilizing an ion source, a vacuum system with at least one vacuum stage, at least one multipole ion guide which is located in said at least one vacuum stages, and a Time-of-Flight mass analyzer, said Time-of-Flight mass analyzer having a pulsing region comprising lens elements, a Time-of-Flight tube, and a detector;
(b) producing ions from a sample introduced into said ion source;
(c) directing said ions into said at least one multipole ion guide, said at least one multipole ion guide having electrical voltages applied to said at least one multipole ion guide;
(d) transferring said ions through said at least one multipole ion guide and into said pulsing region of said Time-of-Flight mass analyzer; and, (e) applying pulsing voltages to the lens elements in said pulsing region of said Time-of-Flight mass analyzer to accelerate said ions into said Time-of-Flight tube and detecting said ions with said detector.

39. A method according to claim 38, wherein said step of producing said ions is accomplished at substantially atmospheric pressure.

40. A method according to claim 38, wherein said ions are produced with Electrospray ionization.

41. A method according to claim 38, wherein said sample introduced into said ion source is a solution.

42. A method according to claim 38, wherein said ions are produced with nebulizer assisted Electrospray ionization.

43. A method according to claim 38, wherein said ions are produced with Atmospheric Pressure Chemical Ionization.

44. A method according to claim 38, wherein said ions are produced Inductively Coupled Plasma ionization.

45. A method according to claim 38, wherein said ions are directed into said pulsing region with a trajectory substantially orthogonal to said Time-of-Flight tube axis.

46. A method according to claim 38, wherein said ions are directed into said pulsing region with a trajectory substantially in line with said Time-of-Flight tube axis.

47. A method according to claim 38, further comprising the step of maintaining the pressure in at least a portion of said at least one multipole ion guide at a level sufficiently high to cause multiple collisions to occur between said ions and neutral background gas molecules within said portion of said multipole ion guide resulting in reduction of kinetic of said ions.

48. A method according to claim 38, further comprising the step of maintaining a background pressure of at least 1 millitorr in at least one of said vacuum stages in which a portion of said at least one multipole ion guide is located.

49. A method according to claim 38, further comprising the step of maintaining a background pressure of at least 50 millitorr in at least one of said vacuum stages in which a portion of said at least one multipole ion guide is located.

50. A method according to claim 38, further comprising the step of maintaining a background pressure of at least 100 millitorr in at least one of said vacuum stages in which a portion of said at least one multipole ion guide is located.

51. A method according to claim 38, further comprising the step of maintaining a background pressure of at least 150 millitorr in at least one of said vacuum stages in which a portion of said at least one multipole ion guide is located.

52. A method according to claim 38, wherein said electrical voltages applied to said at least one multipole ion guide comprise AC & DC components, and further comprising the step of applying said electrical voltages comprising AC and DC
components to said at least one multipole ion guide to establish the energy of said ions exiting from said at least one multipole ion guide.

53. A method according to claim 38, wherein said electrical voltages applied to said at least one multipole ion guide comprise AC & DC components, and further comprising the step of applying said electrical voltages comprising AC and DC
components to said at least one multipole ion guide to limit the mass-to-charge range of said ions which will pass through said at least one multipole ion guide.

54. A method according to claim 52 or 53, whereby the analysis capability of said Time-of-Flight mass analyzer is enhanced.

55. A method according to claim 52 or 53, whereby the detector response of said Time-of-Flight mass analyzer is enhanced.

56. An apparatus for analyzing chemical species, comprising:
(a) an ion source for producing ions from a sample substance, said ion source operating at substantially atmospheric pressure (b) a vacuum region, said vacuum region comprising at least one vacuum stage, said at least one vacuum stage having means for pumping away gas to produce a partial vacuum;
(c) a Time-of-Flight mass analyzer, said Time-of-Flight mass analyzer being located in at least one of said at least one vacuum stage;
(d) at least one multipole ion guide, said at least one multipole ion guide being located in said vacuum region;
and (e) means for applying electrical voltages to said at least one multipole ion guide.

57. An apparatus according to claim 56, wherein said vacuum region comprises at least two vacuum stages, said vacuum stages being in communication with each other such that said ions can move through a sequence of said vacuum stages.

58. An apparatus according to claim 56 or 57, wherein the first of said vacuum stages is in communication with said ion source such that said ions produced by said ion source can move from said ion source into said first of said at least one vacuum stage.

59. An apparatus according to claim 56, 57 or 58, wherein said Time-of-Flight mass analyzer comprises an ion pulsing region and a Time-of-Flight tube.

60. An apparatus according to claim 59, wherein said Time-of-Flight mass analyzer is configured for orthogonal pulsing of said ions from said pulsing region into said Time-of-Flight tube.

61. An apparatus according to claim 59, wherein said Time-of-Flight mass analyzer is configured for in-line pulsing of said ions from said pulsing region into said Time-of-Flight tube.

62. An apparatus according to claim 59, wherein said Time-of-Flight mass analyzer further comprises an ion trap for pulsing of said ions from said pulsing region into said Time-of-Flight tube.

63. An apparatus according to claim 56, 57, 58 or 59, wherein said ion source produces ions from solution and delivers said ions into said vacuum region through an orifice.

64. An apparatus according to claim 56, 57, 58 or 59, wherein said at least one multipole ion guide is a hexapole.

65. An apparatus according to claim 56, 57, 58 or 59, wherein said at least one multipole ion guide is a quadrupole.

66. An apparatus according to claim 56, 57, 58 or 59, wherein said at least one multipole ion guide has more than six poles.

67. An apparatus according to claim 56, 57, 58 or 59, wherein said means of applying electrical voltages to said at least one multipole ion guide includes the application of AC and DC
voltages to said at least one multipole ion guide.

68. An apparatus according to claim 67, wherein said AC and DC voltages and the AC frequency are adjustable.

69. An apparatus according to claim 67, wherein said AC
frequency is fixed, said AC voltage amplitude is adjustable and said DC voltages are adjustable.

70. An apparatus according to claim 68, wherein said AC
frequency and said AC and DC voltages are set to limit the range of mass-to-charge of said ions which can be transmitted through said at least one multipole ion guide.

71. An apparatus according to claim 69, wherein said AC
frequency is fixed and said AC voltage amplitude and said DC
voltages are adjusted to limit the range of mass-to-charge of ions which can be transmitted through said at least one multipole ion guide.

72. An apparatus according to claim 68 or 69, wherein said AC
and DC voltages are adjusted to increase the duty cycle of said Time-of-Flight mass analyzer.

73. An apparatus according to claim 68 or 69, wherein said AC
and DC voltages are adjusted to select the energy of said ions entering said Time-of-Flight mass analyzer.

74. An apparatus according to claim 68 or 69, wherein said Time-of-Flight mass analyzer further comprises a Time-of-Flight detector, and wherein said AC and DC voltages are adjusted to decrease said detector dead time of said Time-of-Flight mass analyzer.

75. An apparatus according to claim 56, 57, 58 or 59, wherein at least one of said multipole ion guides is located in one of said vacuum stages such that it begins and ends in the same vacuum stage.

76. An apparatus according to claim 56, 57, 58 or 59, each of said multipole ion guides in each of said vacuum stages begins and ends within its respective vacuum stage.

77. An apparatus according to claim 56, 57, 58 or 59, wherein at least one of said multipole ion guides begins in one of said vacuum stages and extends into at least one subsequent vacuum stage.

78. An apparatus according to claim 56, 57, 58 or 59, wherein at least a portion of said at least one multipole ion guide is located in at least one said vacuum stage within said vacuum region where the background pressure is sufficiently high such that multiple collisions occur between ions and background gas in said at least one multipole ion guide.

79. An apparatus according to claim 56, 57, 58 or 59, wherein the background pressure in at least one of said vacuum stages where at least a portion of said at least one multipole ion guide is located is sufficiently high to cause multiple collisions to occur between said ions and neutral background gas molecules within said portion of said multipole ion guide resulting in reduction of kinetic energy of said ions.

80. An apparatus according to claim 56, 57, 58 or 59, wherein at least one of said vacuum stages into which said multipole ion guide extends is maintained at a background pressure of at least 1 millitorr.

81. An apparatus according to claim 80, wherein said background pressure is at least 50 millitorr.

82. An apparatus according to claim 80, wherein said background pressure is at least 100 millitorr.

83. An apparatus according to claim 80, wherein said background pressure is at least 150 millitorr.

84. An apparatus of claim 56, 57, 58 or 59, wherein each successive vacuum pumping stage in said sequence of said vacuum stages has a lower background pressure than the previous pumping stage.

85. An apparatus according to claim 56, 57, 58 or 59, wherein the radial distance from the inner surface of a pole of said at least one multipole ion guide to the centerline of said at least one multipole ion guide is not greater than 1.5 millimeters.

86. An apparatus according to claim 56, 57, 58 or 59, wherein the radial distance from the inner surface of a pole of said at least one multipole ion guide to the centerline of said at least one multipole ion guide is not greater than 1.0 millimeters.

87. An apparatus according to claim 56, 57, 58 or 59, wherein the radial distance from the inner surface of a pole of said at least one multipole ion guide to the centerline of said at least one multipole ion guide is not greater than 2.5 millimeters.

88. An apparatus according to claim 56, 57, 58 or 59, wherein said ion source is an Electrospray ion source.

89. An apparatus according to claim 56, 57, 58 or 59, wherein said ion source is an Atmospheric Pressure Chemical Ionization source.

90. An apparatus according to claim 56, 57, 58 or 59, wherein said ion source is an Inductively Coupled Plasma ion source.

91. An apparatus according to claim 56, 57, 58 or 59, wherein said ion source is an Electrospray ion source with pneumatic nebulization assist.

92. A method of analyzing chemical species, comprising:
(a) utilizing an ion source operated substantially at atmospheric pressure, a vacuum system with at least one vacuum stage, at least one multipole ion guide which is located in at least one of said vacuum stages, and a Time-of-Flight mass analyzer;

(b) producing ions from a sample introduced into said ion source;
(c) directing said ions into said at least one multipole ion guide, said at least one multipole ion guide having electrical voltages applied to said at least one multipole ion guide; and (d) transferring said ions through said at least one multipole ion guide and directing said ions into said Time-of-Flight mass analyzer for Time-of-Flight mass analysis of said ions.

93. A method according to claim 92, wherein said sample introduced into said ion source is a solution.

94. A method according to claim 92, wherein said ions are produced with Electrospray ionization.

95. A method according to claim 92, wherein said ions are produced with nebulizer assisted Electrospray ionization.

96. A method according to claim 92, wherein said ions are produced with Atmospheric Pressure Chemical Ionization.

97. A method according to claim 92, wherein said ions are produced with Inductively Coupled Plasma ionization.

98. A method according to claim 92, wherein said Time-of-Flight analyzer comprises a pulsing region comprising lens elements, and a Time-of-Flight tube, and the step of transferring said ions through said at least one multipole ion guide and directing said ions into said pulsing region of said Time-of-Flight mass spectrometer.

99. A method according to claim 98, further comprising the step of applying pulsing voltages to the lens elements in said pulsing region to accelerate said ions into said Time-of-Flight tube from said pulsing region.

100. A method according to claim 99, wherein said ions are directed into said pulsing region with a trajectory substantially orthogonal to the direction of said acceleration.

101. A method according to claim 99, wherein said ions are directed into said pulsing region with a trajectory substantially in line with the direction of said acceleration.

102. A method according to claim 92, further comprising the step of maintaining the pressure in at least a portion of said at least one multipole ion guide at a level sufficiently high to cause multiple collisions to occur between said ions and neutral background gas molecules within said portion of said multipole ion guide resulting in reduction of kinetic energy of said ions.

103. A method according to claim 92, further comprising the step of maintaining a background pressure of at least 1 millitorr in at least one of said vacuum stages in which a portion of said at least one multipole ion guide is located.

104. A method according to claim 92, further comprising the step of maintaining a background pressure of at least 50 millitorr in at least one of said vacuum stages in which a portion of said at least one multipole ion guide is located.

105. A method according to claim 92, further comprising the step of maintaining a background pressure of at least 100 millitorr in at least one of said vacuum stages in which a portion of said at least one multipole ion guide is located.

106. A method according to claim 92, further comprising the step of maintaining a background pressure of at least 150 millitorr in at least one of said vacuum stages in which a portion of said at least one multipole ion guide is located.

107. A method according to claim 92, wherein said electrical voltages applied to said at least one multipole ion guide comprise AC & DC components, and further comprising the step of applying said electrical voltages comprising AC and DC
components to said at least one multipole ion guide to establish the energy of said ions exiting from said at least one multipole ion guide.

108. A method according to claim 92, wherein said electrical voltages applied to said at least one multipole ion guide comprise AC & DC components, and further comprising the step of applying said electrical voltages comprising AC and DC
components to said at least one multipole ion guide to limit the mass-to-charge range of said ions which will pass through said at least one multipole ion guide.

109. A method according to claim 107 or 108, whereby the analysis capability of said Time-of-Flight mass analyzer is enhanced.

110. A method according to claim 107 or 108, wherein said Time-of-Flight mass analyzer further comprises a Time-of-Flight detector, and whereby the detector response of said Time-of-Flight mass detector is enhanced.