Atmospheric Pressure Ionization in a Miniature Mass Spectrometer

Anal. Chem. 2005, 77, 2928-2939

Atmospheric Pressure Ionization in a Miniature Mass Spectrometer Brian C. Laughlin, Christopher C. Mulligan, and R. Graham Cooks*

Department of Chemistry, Purdue University, West Lafayette, Indiana 47907-2084

A miniature cylindrical ion trap mass spectrometer featuring an atmospheric pressure interface allowing atmospheric pressure chemical ionization and electrospray ionization is described together with its analytical performance characteristics. The vacuum system, ion optics, mass analyzer, control electronics system, and detection system have all been designed and built in-house. The design is based upon a three-stage, differentially pumped vacuum system with the instrument capable of being interfaced to many types of atmospheric pressure ionization sources. Ions are transferred through home-built ion optics, and instrument control is achieved through customdesigned electronics and LabView control software. Corona discharge ionization and electrospray ionization sources are implemented and used to allow the analysis of both gaseous- and solution-phase samples during the characterization of the instrument. An upper mass/charge limit of ∼450 Th with unit resolution was achieved using a 2.5-mm-internal radius cylindrical ion trap as the mass analyzer. The specificity of the instrument can be increased by employing the MS/MS capabilities of the ion trap and has been demonstrated for nitrobenzene. Limits of detection for the trace analysis in air of the chemical warfare agent simulant methyl salicylate (1.24 ppb) and for nitrobenzene (629 pptr) are achieved. The dynamic range of the instrument is currently limited to ∼2 orders of magnitude by saturation of the detection electronics. Isolation and collision-induced dissociation efficiencies in MS/MS experiments both greater than 50% are reported. Electrospray/nanospray data are presented on solutions including 100 µΜ (D,L)-arginine, 10 µM (-)ephedrine, and 10 µM lomefloxacin. There are a variety of practical, compelling reasons to develop methods for the rapid detection of chemical species in air and water at trace levels with high specificity. This objective is being pursued through the development of fieldable analytical instrumentation for in situ detection of chemical compounds. Performing chemical analysis in situ can be advantageous in areas such as industrial hygiene, environmental monitoring, and chemical process monitoring and is crucial for the early warning of a chemical release. Because mass spectrometry is the “gold standard” analytical method, widely recognized for sensitivity, * To whom correspondence should be addressed. Telephone: (765) 494-5262. Fax: (765) 494-9421. E-mail: [email protected].

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selectivity, and broad applicability, efforts to miniaturize mass spectrometers are receiving considerable attention. Miniaturization of the mass spectrometer must begin with miniaturization of the core component of the mass spectrometer, the mass analyzer. Miniaturization has been investigated for nearly all mass analyzers, including the quadrupole ion trap,1-7 ion cyclotron resonance,8,9 time of flight,10-15 magnetic sector,16-18 and linear quadrupole.19-21 The subject was the focus of a recent review.22 Quadrupole ion traps have particular advantages as miniaturized instruments since they operate at higher pressures than other mass analyzers (relaxing requirements for developing miniature high-vacuum pumps). A series of miniature instruments has been built in this laboratory based on miniature cylindrical ion trap (CIT) mass analyzers and utilizing electron impact ionization (EI) or chemical ionization (CI).23 Samples are introduced by membrane introduc(1) Kaiser, R. E.; Cooks, R. G.; Stafford, G. C.; Syka, J. E. P.; Hemberger, P. H. Int. J. Mass Spectrom. Ion Processes 1991, 106, 79-115. (2) Badman, E. R.; Cooks, R. G. Anal. Chem. 2000, 72, 3291-3297. (3) Badman, E. R.; Johnson, R. C.; Plass, W. R.; Cooks, R. G. Anal. Chem. 1998, 70, 4896-4901. (4) Kornienko, O.; Reilly, P. T. A.; Whitten, W. B.; Ramsey, J. M. Rev. Sci. Instrum. 1999, 70, 3907-3909. (5) Kornienko, O.; Reilly, P. T. A.; Whitten, W. B.; Ramsey, J. M. Rapid Commun. Mass Spectrom. 1999, 13, 50-53. (6) Moxom, J.; Reilly, P. T. A.; Whitten, W. B.; Ramsey, J. M. Rapid Commun. Mass Spectrom. 2002, 16, 755-760. (7) Peddanenikalva, H.; Potluri, K.; Bhansali, S.; Short, R. T.; Fries, D. In IEEE Sensors 2002, IEEE International Conference on Sensors, Orlando, FL, June 12-14, 2002; pp 651-655. (8) Miller, G.; Koch, M.; Hsu, J. P.; Ozuna, F. In 45th ASMS Conference on Mass Spectrometry and Allied Topics, Palm Springs, CA, 1997. (9) Prieto, M. C.; Dietrich, D.; Keville, R.; Hopkins, D. In 45th ASMS Conference on Mass Spectrometry and Allied Topics, Palm Springs, CA, 1997. (10) Cotter, R. J.; Cornish, T. J. J. Mass Spectrom. 1999, 34, 1368-1372. (11) Berkout, V. D.; Cotter, R. J.; Segers, D. P. J. Am. Soc. Mass Spectrom. 2001, 12, 641-647. (12) Cornish, T. J.; Ecelberger, S.; Brinckerhoff, W. Rapid Commun. Mass Spectrom. 2000, 14, 2408-2411. (13) Prieto, M. C.; Cotter, R. J. J. Mass Spectrom. 2002, 37, 1158-1162. (14) English, R. D.; Cotter, R. J. J. Mass Spectrom. 2003, 38, 296-304. (15) Gardner, B. D.; Cotter, R. J. In Abstracts of Papers, 225th ACS National Meeting, New Orleans, LA, March 23-27, 2003; ANYL-231. (16) Diaz, J. A.; Giese, C. F.; Gentry, W. R. Field Anal. Chem. Technol. 2001, 5, 156-167. (17) Diaz, J. A.; Giese, C. F.; Gentry, W. R. J. Am. Soc. Mass Spectrom. 2001, 12, 619-632. (18) Sinha, M. P.; Tomassian, A. D. Rev. Sci. Instrum. 1991, 62, 2618-2620. (19) Taylor, S.; Srigengan, B.; Gibson, J. R.; Tindall, D.; Syms, R. R. A.; Tate, T.; Ahmad, M. M. Proc. SPIE-Int. Soc. Opt. Eng. 2000, 187-193. (20) Orient, O. J.; Chutjian, A.; Garkanian, V. Rev. Sci. Instrum. 1997, 68, 13931397. (21) Boumsellek, S.; Ferran, R. J. J. Am. Soc. Mass Spectrom. 2001, 12, 633640. (22) Badman, E. R.; Cooks, R. G. J. Mass Spectrom. 2000, 35, 659-671. 10.1021/ac0481708 CCC: $30.25

© 2005 American Chemical Society Published on Web 03/26/2005

tion mass spectrometry inlets24,25 or the more recent fiber introduction systems.26,27 These instrument systems have shown good sensitivity in both MS and MS/MS experiments on air and water samples. This paper details the design, construction, and initial characterization of a new, miniature CIT mass spectrometer system, which utilizes atmospheric pressure ionization (API) sources. API encompasses a number of powerful ionization methods in mass spectrometry, some well suited to air analysis and others to aqueous solution analysis. The particular API sources used are atmospheric pressure chemical ionization (APCI) and electrospray ionization (ESI). The work represents a further extension of an already intensive program in the development of miniaturized mass spectrometers based on ion trapping instruments, for the determination of chemical compounds in situ from complex mixtures in air and water matrixes. The difficulty of handling large volumes of air or water vapor in a miniature instrument makes this instrument development project a challenging undertaking. Previously, miniature mass spectrometers have often been built with EI ion sources, an attractive ionization method for use in miniature instruments as the pumping speed requirement of the high-vacuum pump is considerably lower than in the case of API instruments. EI also has the benefits of being highly reproducible, inexpensive, and rugged, as well as requiring little power to operate. However, it suffers from the complexity of the data generated when analyzing complex mixtures without the use of selective sample inlets or chromatographic separations and is not applicable to the ionization of some compounds of particular interest in field analysis. Several commercial miniature mass spectrometers have been developed using EI sources. Griffin Analytical Technologies, Inc. (West Lafayette, IN) has recently released a field-ready miniature gas chromatography/mass spectrometer (GC/MS) instrument that utilizes an EI/CI source and is based upon the CIT mass analyzer. A portable mass spectrometerbased helium leak detector, also using a CIT, has been developed by MKS Instruments (Wilmington, MA). Finally, Inficon (East Syracuse, NY) has developed a portable GC/MS EI instrument based on a miniaturized linear quadrupole array for on-site chemical hazard identification. Among other ionization sources coupled to miniature mass spectrometers, Cotter and co-workers have demonstrated the use of matrix-assisted laser desorption ionization coupled with a miniature time-of-flight mass spectrometer,10,14,15 allowing for the analysis of solid matrixes and molecules of biological origin. Syagen Technology, Inc. (Tustin, CA) has released a fieldable gas chromatograph-quadrupole ion trap/time-of-flight mass spectrometer28 utilizing a reduced pressure photoionization source. Pho(23) Patterson, G. E.; Guymon, A. J.; Riter, L. S.; Everly, M.; Griep-Raming, J.; Laughlin, B. C.; Ouyang, Z.; Cooks, R. G. Anal. Chem. 2002, 74, 61456153. (24) Riter, L. S.; Laughlin, B. C.; Nikolaev, E.; Cooks, R. G. Rapid Commun. Mass Spectrom. 2002, 16, 2370-2373. (25) Riter, L. S.; Peng, Y.; Noll, R. J.; Patterson, G. E.; Aggerholm, T.; Cooks, R. G. Anal. Chem. 2002, 74, 6154-6162. (26) Meurer, E. C.; Tomazela, D. M.; Silva, R. C.; Augusto, F.; Eberlin, M. N. Anal. Chem. 2002, 74, 5688-5692. (27) Riter, L. S.; Meurer, E. C.; Cotte-Rodriguez, I.; Eberlin, M. N.; Cooks, R. G. Analyst 2003, 128, 1119-1122. (28) Syage, J. A.; Hanning-Lee, M. A.; Hanold, K. A. Field Anal. Chem. Technol. 2000, 4, 204-215.

toionization, particularly at atmospheric pressure,29 can be beneficial in field studies of complex mixtures because photoionization deposits a characteristic amount of energy, selectively ionizing compounds of low ionization energy and doing so with small excess energies, thus minimizing fragmentation. APCI is an technique characterized by its simplicity, speed, sensitivity, and wide range of applicability.30,31 First reported by Horning et al.,32 it was developed by Henion and co-workers33 as well as others34-36 as an interface for LC-MS. Early APCI sources used in mass spectrometry as well as those used in portable IMS instruments employed radioactive 63Ni sources to generate the primary reagent ions; however, corona discharge has now largely replaced the 63Ni source for mass spectrometry and is also doing so for ion mobility spectrometry.37-44 A typical APCI system utilizes reagent ions formed in an electrical discharge in the surrounding gas to ionize the sample through ion/molecule reactions or through reagent dopants added to increase the specificity/ sensitivity for particular analytes of interest.45 APCI allows control of molecule fragmentation and specificity of ionization, as well as allowing direct air monitoring without the need for a membrane sampling interface. At atmospheric pressure, the large number of collisions between reagent ions and analyte molecules leads to a higher ionization efficiency than in a conventional reducedpressure CI source, potentially increasing the sensitivity of API instruments over those that use reduced pressure ionization. Ionization at atmospheric pressure, followed by direct mass spectrometric analysis (as well as tandem mass spectrometric analysis), is a logical approach to maximize sensitivity in trace ambient air analysis. The ability to directly sample ions generated at atmospheric pressure through an atmospheric interface would be particularly useful for a fieldable miniature instrument. The ion/molecule reactions that occur during air analysis by APCI predominantly result in protonated water clusters (in the absence of a dopant), especially under high-humidity conditions,46,47 and these primary ions serve as the proton carriers for chemical ionization. The series of water cluster ions produced in (29) Raffaelli, A.; Saba, A. Mass Spectrom. Rev. 2003, 22, 318-331. (30) Abian, J. J. Mass Spectrom. 1999, 34, 157-168. (31) Niessen, W. M. A. J. Chromatogr., A 1998, 794, 407-435. (32) Horning, E. C.; Horning, M. G.; Carroll, D. I.; Dzidic, I.; Stillwell, R. N. Anal. Chem. 1973, 45, 936-943. (33) Covey, T. R.; Lee, E. D.; Bruins, A. P.; Henion, J. D. Anal. Chem. 1986, 58, 1451A-1461A. (34) Garcia, D. M.; Huang, S. K.; Stansbury, W. F. J. Am. Soc. Mass Spectrom. 1996, 7, 59-65. (35) Kambara, H. Anal. Chem. 1982, 54, 143-146. (36) Dzidic, I.; Carroll, D. I.; Stillwell, R. N.; Horning, E. C. Anal. Chem. 1976, 48, 1763-1768. (37) Xu, J.; Whitten, W. B.; Ramsey, J. M. Anal. Chem. 2003, 75, 4206-4210. (38) Borsdorf, H.; Nazarov, E. G.; Eiceman, G. A. J. Am. Soc. Mass Spectrom. 2002, 13, 1078-1087. (39) Borsdorf, H.; Rammler, A.; Schulze, D.; Boadu, K. O.; Feist, B.; Weiss, H. Anal. Chim. Acta 2001, 440, 63-70. (40) Borsdorf, H.; Schelhorn, H.; Flachowsky, J.; Doring, H. R.; Stach, J. Anal. Chim. Acta 2000, 403, 235-242. (41) Hill, C. A.; Thomas, C. L. P. Analyst 2003, 128, 55-60. (42) Khayamian, T.; Tabrizchi, M.; Jafari, M. T. Talanta 2003, 59, 327-333. (43) Tabrizchi, M.; Khayamian, T.; Taj, N. Rev. Sci. Instrum. 2000, 71, 23212328. (44) Stach, J.; Baumbach, J. I. Int. J. Ion Mobility Spectrom. 2002, 5, 1-21. (45) Raffaelli, A. In Selected Topics and Mass Spectrometry in the Biomolecular Sciences; Caprioli, R. M., Malorni, A., Sindona, G., Eds.; Kluwer Academic Publishers: Amsterdam, 1997; pp 17-31. (46) Pavlik, M.; Skalny, J. D. Rapid Commun. Mass Spectrom. 1997, 11, 17571766.

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positive ionization mode are of the form H+(H2O)n.48-50 The number and intensity of these cluster ions is influenced by changes in temperature, humidity, and distance between the corona discharge tip and the entrance to the mass spectrometer. In the presence of molecules of high proton affinity, protonated molecules will be formed and will tend to dominate the positive ion spectrum while analytes with high electron affinity, gas-phase acidity, or both will dominate in the negative ion mode. The initial description of the present instrument appearing in conference proceedings51,52 and a recently published example of a miniature mass spectrometer using an APCI source interfaced to a monopole mass analyzer53 represent the first descriptions of atmospheric pressure ionization miniature instruments. There are special vacuum requirements when coupling source pressures of ∼760 Torr with a typical mass analyzer at pressure of ∼10-5 Torr. With instrument sensitivity largely based on the size of the initial ion sampling aperture, maintaining good performance requires the ion sampling aperture to be as large as possible while maintaining a pressure differential of ∼8 orders of magnitude. In situations where the use of API is advantageous, a mass analyzer capable of operation at high pressures can reduce demands on the pumping system. Quadrupole ion traps are unique in that they not only tolerate but require the use of a relatively high pressure (∼1 mTorr) buffer gas to obtain the best sensitivity and resolution. For in situ detection of chemical species present in complex matrixes, a tandem mass spectrometric capability is also desired. For this reason, together with the fact that the simplified electrode geometry of the CIT allows for the ready miniaturization of the ion trap, the CIT has been chosen as the basis for all of the miniaturization efforts described by this laboratory thus far. The optimization of the CIT for use as a mass spectrometer began with the demonstration of the so-called full-sized CIT54 (inscribed radius 1 cm) operated in the mass selective instability mode.55 The earliest work focused on the reduction in the size of the mass analyzer, and it resulted in mass analyzers on the millimeter internal radius size scale.3,5 The full-sized CIT exhibited performance characteristics similar to, but not quite as good as those of a standard (Paul) quadrupole ion trap in terms of resolution, mass range, mass accuracy, and mass linearity, as well as retaining tandem mass spectrometric capabilities. Although miniaturized CITs suffer some loss in performance when compared to full-sized CITs in both our studies and those performed by others,4-6,56 their performance has proved to be adequate for many experiments.

The advantages of a miniaturized ion trap can be seen through a rearrangement of the equation for the dimensionless Mathieu stability parameter q (eq 1), where Vrf is the amplitude of the

(47) Nikolaev, E.; Riter, L. S.; Laughlin, B. C.; Handberg, E.; Cooks, R. G. Eur. J. Mass Spectrom. 2004, 10, 197-204. (48) Kebarle, P.; Godbole, E. W. J. Chem. Phys. 1963, 39, 1131-1132. (49) Fehsenfeld, F. C.; Mosesman, M.; Ferguson, E. E. J. Chem. Phys. 1971, 55, 2120-2125. (50) Fehsenfeld, F. C.; Mosesman, M.; Ferguson, E. E. J. Chem. Phys. 1971, 55, 2115-2119. (51) Laughlin, B. C.; Johnson, P. V.; Beegle, L. W.; Kanik, I.; Cooks, R. G. In 51st ASMS Conference on Mass Spectrometry and Allied Topics, Montreal, Canada, 2003. (52) Laughlin, B. C.; Mulligan, C. C.; Cooks, R. G. In 52nd ASMS Conference on Mass Spectrometry and Allied Topics, Nashville, TN, 2004. (53) Makas, A. L.; Troshkov, M. L.; Kudryavtsev, A. S.; Lunin, V. M. J. Chromatogr., B 2004, 800, 63-67. (54) Wells, J. M.; Badman, E. R.; Cooks, R. G. Anal. Chem. 1998, 70, 438-444. (55) Stafford, G. C.; Kelley, P. E.; Syka, J. E. P.; Reynolds, W. E.; Todd, J. F. J. Int. J. Mass Spectrom. Ion Processes 1984, 60, 85-98.

EXPERIMENTAL SECTION The description of the instrument is broken into sections that describe the major subsystems and components. Figure 1 shows the major components and subsystems of the instrument along with their interrelationships. Vacuum System. Perhaps the most critical component of a miniature mass spectrometer is the vacuum system, typically the largest, heaviest, and most power-hungry system in a mass

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(m/z)max ) 8Vrf/qejro2Ω2

(1)

applied rf voltage (0-peak), qej is the chosen value of qz for ion ejection, ro is the inscribed radius of the ion trap, and Ω is the angular frequency of the rf drive voltage. With the appropriate choice of operational parameters for the ion trap, i.e., rf frequency, trap size, and rf voltage range, this relationship allows a reduction in rf voltage while maintaining the same mass range for a miniaturized ion trap. In turn, the size and especially the power of the electronics system necessary to generate the high-voltage rf can also be reduced. Although a reduction in voltage is attractive, a lower voltage reduces the effectiveness of ion trapping by reducing the depth of the psuedopotential well in which ions are trapped. The psuedopotential trapping well57 in the axial (z) direction is given by eq 2 (for qz < 0.4). Much of the previous

Dz ) qzVrf/8

(2)

research with miniature CITs has used ionization methods that generate ions inside of the ion trapping volume with little translational energy. Injection of ions formed externally into the ion trapping volume is more difficult and requires inter alia that the ion’s translational energy be smaller than the psuedopotential well depth or that it be efficiently reduced by collisions as the ion enters the trap. As a consequence of the reduced potential well depth in a miniaturized device, a tradeoff in the operating frequency and rf voltage (and hence mass range) must be made to ensure efficient ion trapping as well as low power consumption. A tradeoff in the choice of the size of the analyzer may also be needed because the lower rf voltage and hence power demands of smaller traps might be offset by the proportionately larger machining errors, which can lead to undesirable faults in the trapping field. Ions generated in an external EI/CI source have been trapped in a miniature CIT,58,59 but trapping of ions generated in an atmospheric pressure ionization source has not yet been described. The research presented here represents the first coupling of atmospheric pressure ionization sources to a miniature ion trap. The instrument described has been constructed to be small in overall size with attention paid to portability and ruggedness.

(56) Kornienko, O.; Reilly, P. T. A.; Whitten, W. B.; Ramsey, J. M. Anal. Chem. 2000, 72, 559-562. (57) Major, F. G.; Dehmelt, H. G. Phys. Rev. 1968, 170, 91-107. (58) Tabert, A. M.; Misharin, A. S.; Cooks, R. G. Analyst 2004, 129, 323-330. (59) Tabert, A. M.; Griep-Raming, J.; Guymon, A. J.; Cooks, R. G. Anal. Chem. 2003, 75, 5656-5664.

Figure 1. Schematic diagram of the miniature CIT mass spectrometer showing the major instrument components and subsystems as well as their interrelationships.

spectrometer. This is especially true for instruments utilizing atmospheric pressure ionization sources where large volumes of gases must be handled. A three-stage vacuum system with a heated capillary ion inlet was designed for this instrument, a common choice for instruments with an atmospheric pressure inlet. Ions generated using an API source are passed into the vacuum system through a 254-µm-inner diameter, 5-cm-long stainless steel capillary tube (Alltech Associates, Inc., Deerfield, IL). The capillary is held in place by an aluminum holder, which can be heated to assist in the desolvation of cluster ions formed in the API source and is sealed to the front of the vacuum manifold using a Viton O-ring (McMaster-Carr Supply Co., Chicago, IL). The capillary also serves to limit the gas input into the first vacuum stage of the instrument to ∼4.5 Torr L/s. The first vacuum stage is evacuated using a small rotary vane pump (∼18 m3/h, SD 2021, Alcatel Vacuum Products, Inc., Hingham, MA) to a pressure of ∼700 mTorr as measured using a Convectron pressure gauge (series 275, Helix Technology Corp., Longmont, CO). The end of the inlet capillary is held coaxially with and 2.75 mm from a skimmer of 500-µm diameter that serves to sample ions exiting the capillary as well as to limit the gas transmitted into the second vacuum stage. The second and third vacuum stages are each evacuated using Alcatel ATH-31+ turbomolecular pumps, both of which provide pumping speeds of ∼30 L/s. The turbomolecular pumps are powered from the 24-V bus using miniaturized controllers (ATH 201 H) available from Alcatel. The multiple Holweck drag stages in the turbomolecular pump provide a high compression ratio that permits the pump to exhaust to higher pressures (up to ∼30 Torr) than other turbomolecular pumps. As a result, each pump is backed only by a small two-stage KNF Neuberger, Inc. (N84.0, Trenton, NJ) diaphragm pump. The base pressures in the second and third stages are 4 mTorr and 2 × 10-5 Torr, respectively, as measured using Bayard-Alpert-type ionization gauges (series 354, Helix Technology Corp.). Gas transmission between the second and third stages is limited by a 1-mm aperture, which separates the individual chambers. During

Figure 2. Illustration of the vacuum manifold and three-stage differentially pumped vacuum system. The two-stage diaphragm pumps that back each turbomolecular pump are not shown.

instrument operation, room air is leaked into the third vacuum stage through a needle metering valve (4A-H0L-V-SS-TC, Parker Hannifin Corp., Jacksonville, AL) to a typical indicated pressure of 1 mTorr to improve ion trapping efficiency and mass resolution. The vacuum system is shown in Figure 2. The vacuum manifold was designed around custom ion optics to be compact and lightweight. The manifold was machined from solid aluminum stock and provides the three differentially pumped vacuum chambers, as well as mounting locations for the ion optics and external flanges for electrical and gas feed-throughs. Ion Optics. In miniaturized mass spectrometers, ion optical and vacuum pumping considerations lead one to select ion sampling apertures that are small compared to those in laboratoryscale instruments. Efficient ion transfer through the various Analytical Chemistry, Vol. 77, No. 9, May 1, 2005

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Table 1. Operating Conditions for the Miniature CIT Mass Spectrometera pressures

first vacuum stage second vacuum stage third vacuum stage Figure 3. Schematic diagram of the ion optics and its relationship to the three-stage vacuum system.

vacuum stages of the instrument is, therefore, the key to successful operation. Many elements of ion optical design embodied in commercial instruments were incorporated into the overall ion optical design of this instrument. The overall ion optical design is shown in Figure 3. Ions generated at atmospheric pressure are drawn into the vacuum system through the capillary inlet. In the first vacuum stage, ions exiting the capillary are focused onto the 500-µm-diameter aperture of the skimmer using a tube lens.60 The capillary is held coaxially to the skimmer at a separation distance of ∼2.75 mm. This value was chosen as the optimum distance for sufficient ion transfer through the skimmer, while minimizing gas transfer into the next vacuum stage. Ions passing from the first vacuum chamber into the second are captured by an rf-only quadrupole ion guide,61,62 where they are collisionally cooled and focused onto the center axis, i.e., on the pseudopotential well formed through the application of a bipolar rf voltage. A square rod quadrupole63 (ThermoElectron Corp., San Jose, CA) was used to perform this function. The device is a traditional quadrupole ion guide except that the rods are rectangular rather than hyperbolic or circular in cross section. Since it is not used for mass analysis, a high-quality quadrupolar field is not necessary. The square rod quadrupole provides a sufficiently close approximation to a quadrupolar field in an easily constructed device. Ions traversing the length of the ion guide are passed through the 1-mm-diameter aperture separating the second and third vacuum stages before being focused onto the entrance aperture of the CIT using an einzel lens (Figure 3). All customdesigned ion optics were fabricated in-house. The fabricated ion optical components were machined from stainless steel and are separated using polyetheretherketone (PEEK, Victrex USA Inc., Greenville, SC) insulators and spacers. Alignment between components in the first two vacuum stages is made through the use of locating pins in the vacuum manifold. Alignment of the einzel lens, CIT, and detector is performed by mounting these components on precision-ground ceramic rods. Typical operating parameters when performing experiments can be found in Table 1. Cylindrical Ion Trap Mass Analyzer. The CIT used in this instrument is based on an earlier design59 that has been shown to perform well. The analyzer is machined from stainless steel and has been designed to have a small overall size and minimized ion trap capacitance. The ion trap has an inscribed radius (ro) of (60) Mylchreest, I. C.; Hail, M. E.; Herron, J. R. Finnigan Corp., U.S. Patent 5,157,260, 1992. (61) Douglas, D. J.; French, J. B. J. Am. Soc. Mass Spectrom. 1992, 3, 398-408. (62) Miller, P. E.; Denton, M. B. Int. J. Mass Spectrom. Ion Processes 1986, 72, 223-238. (63) Khosla, M.; Tehlirian, B. Thermo Finnigan LLC: U.S. Patent 6,441,370, 2002.

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base

operating

680 mTorr 4 mTorr 2 × 10-5 Torr

680 mTorr 4 mTorr 1 mTorr voltages

capillary tube lens skimmer square quadrupole rf square quadrupole frequency square quadrupole dc ion gate open ion gate closed einzel lens element 1 einzel lens element 2 einzel lens element 3 trap float conversion dynode electron multiplier

+25 V +300 V ground 120 V(0-p) 2.42 MHz -0.8 V -8 V +100 V -115 V -6 V -90 V -2.5 Vb -5 kV -1.1 kV

a Voltages are nominal, fine adjustments are made for day-to-day operation. b Trap float voltage reduced to -1.7 V for optimum trapping of high m/z ions.

2.5 mm and a center to end-cap distance (zo) of 2.7 mm. Planar end-cap electrodes machined from 0.75-mm-thick stainless steel allow for ion entrance and egress through 1-mm-radius apertures. The spacing of the end-cap electrodes to the ring electrode is established through the use of 0.79-mm-thick acetal (Delrin, DuPont Co., Wilmington, DE) spacers, with the entire ion trap assembly held together using poly(tetrafluoroethylene) (Teflon, DuPont Co., Wilmington, DE) screws. The cylindrical geometry of the ion trap (as well as the proportionately large end-cap apertures) introduces higher-order field components into the quadrupolar trapping field. The geometry of the CIT used in this instrument has been selected to minimize the effects of the higherorder field content, as determined through simulation and experiment using procedures that have evolved over time.3,64 Electric field calculations using Possion/Superfish code65 were performed to determine the relative content of the higher-order fields in the CIT, and the multiple particle ion trap simulation program, ITSIM 5.0,66 was used to simulate ion motion and calculate mass spectra for particular ion trap geometries. The geometry chosen after optimization adds a small positive octapolar field to compensate for the field faults introduced by the end-cap apertures. The electric fields also allow for the use of a resonance ejection frequency corresponding to the nonlinear octapolar resonance, a mode of operation introduced by Franzen that results in faster ion ejection and improved resolution.67 Instrument Control System. The instrument control computer and hardware is based on a earlier design23 and will therefore (64) Wu, G.; Cooks, R. G.; Ouyang, Z. Int. J. Mass Spectrom. 2005, 241, 119132. (65) Billen, J. H.; Young, L. M. Proc. 1993 Particle Accelerator Conf. 1993, 2, 790-792. (66) Bui, H. A.; Cooks, R. G. J. Mass Spectrom. 1998, 33, 297-304. (67) Franzen, J.; Gabling, R. H.; Schubert, M.; Wang, Y. In Practical Aspects of Ion Trap Mass Spectrometry; March, R. E., Todd, J. F. J., Eds.; CRC Press: Boca Raton, FL, 1995; Vol. 1, pp 49-167.

only be discussed briefly. This system uses National Instruments Corp. (Austin, TX) PCI bus-based instrumentation cards and has been designed to provide flexibility in the operation of the instrument. Four individual cards are used in this system, two PCI-5411 arbitrary waveform generators (ARB), one PCI-MIO16E-1 data acquisition card (DAQ), and one PCI-6602 counter/ timer card. Timing for all timed and switched events occurring during the operation of the instrument is controlled using the counter/timer card. Synchronization of all four devices is also provided by the counter/timer card through the RTSI (real-time system integration) bus. Acquisition of the mass spectral data is performed using the DAQ card, while provisions are made for the direct measurement of the ion gauge pressure using the analog output of the gauge. An rf modulation waveform, used to modulate the amplitude of the high voltage rf drive for the CIT, is generated by one of the two system ARBs. The ARB is equipped with 4 MB of onboard memory and is operated at 400 ksamples/ s, allowing for scan times as long as 5 s. The second system ARB is equipped with 16 MB of onboard memory and is operated at 20 Msamples/s, providing the capability of 0.400 s of waveform playback. Waveforms stored in the ARB’s memory can be sequenced and replayed, allowing for scan times longer than the playback limit. The second ARB is used to generate the waveforms applied to the end-cap electrodes during the operation of the instrument. Software control of the instrument is performed using the same LabView software described previously.23 This software allows complete control over the timing, amplitude, and waveforms applied to the ion trap as well as control over timed events such as ionization, collisional activation, and detector turn-on. The control system was redesigned to take advantage of the small size and reduced power consumption of industrial computer components relative to the ATX-based system previously described. The new system is based on a single board, PCI only, Pentium III computer (ROBO-616, American Portwell Technology, Newark, CA) with a five-slot PCI backplane. Operating under Windows 2000 Professional, this control system is identical to both the ATX control system and the PXI control system used in our previous miniaturized instruments, except that the form factor of the components results in a much smaller system. The computer is completed using a 733-MHz Pentium III processor (Intel Corp., Santa Clara, CA), 256 MB of PC-133 RAM (Kingston Technology Co., Fountain Valley, CA), and a 30-GB notebook hard drive (IBM Corp., White Plains, NY). The control system is housed within an industrial card chassis, which also allows for the mounting of many other electronic components. CIT rf Generation/Amplification. Typical operation of an ion trap mass analyzer requires that a high voltage rf waveform to be applied to the ring electrode of the ion trap. This waveform, termed the drive rf, is typically on the order of 1 MHz and its amplitude is ramped up to a few kV(0-p) in a full-sized ion trap. Since the mass/charge range of an ion trap is directly proportional to the maximum rf amplitude achievable (once the operating frequency has been chosen), it is necessary to generate rf voltages high enough to cover the mass/charge range of interest. The monitoring of ambient air for chemical species is the main design objective of the instrument, thus a mass range of a several hundred thomsons (Th, 1 thomson ) 1 dalton/atomic charge)68 is sufficient.

Generation of the rf applied to the ring electrode begins with a 2.000-MHz crystal oscillator circuit in an rf generation/modulation circuit. The pulsed output of the crystal is shaped into a sinusoidal waveform at 2.000 MHz using a tuned inductive/ capacitive (LC) circuit present on the rf generation/modulation board. In the course of a mass scan, the amplitude of the applied rf is modulated to provide different amplitude levels for ion trapping and auxiliary experiments such as MS/MS, and it is ramped linearly during mass analysis. To perform this modulation, a modulation waveform is generated using one of the two arbitrary waveform generators already mentioned. It then is fed into the rf modulator board to produce the amplitude modulated rf waveform at the output of the board. Amplification of the waveform generated from the rf generation/modulation board is necessary as the maximum voltage available from this circuit is 0-5 V(0-p). Two stages of amplification are used to produce the final rf amplitude needed. The first stage of amplification is performed using a home-built rf power amplifier circuit with an rf power operational amplifier (PA-09, Apex Microtechnology Corp., Tucson, AZ) that can produce a maximum output of ∼35 V(0-p). The output of this amplifier is then used to excite the primary winding of a custom-wound rf transformer in a tuned LC circuit. An LC tank circuit formed from the inductance of the secondary winding of the rf transformer and the capacitance of the ion trap is used to provide the second stage of amplification. The air core, solenoid wound transformer has a secondary wound around a 38.1-mm-outer diameter PVC core consisting of ∼80 turns of 20-gauge magnet wire. The transformer’s primary winding consists of 3 turns of 14-gauge magnet wire wound over the secondary winding, ∼25 mm from the end of the coil. Since the rf frequency is fixed by the use of a crystal oscillator, a 2-12 pF variable capacitor is used for tuning the LC circuit. A capacitive divider is also included in the circuit to permit the measurement of the drive rf voltage. This transformer is able to provide ∼1600 V(0-p), corresponding to an upper mass/charge limit of ∼450 Th. The construction of the rf transformer allows for a dc float potential to be placed on the ring electrode. End-Cap Waveform Generation/Amplification. Secondary waveforms for ion isolation, excitation, and resonance ejection are generated using the second system ARB and are normally applied to the end-cap electrodes of the CIT in a dipolar manner. The output of the ARB is sent to an electronic balun transformer that provides at its output the original waveform and a second, 180deg phase-shifted waveform, with each waveform amplified using a separate power rf amplifier prior to being applied directly to the end-cap electrodes. The maximum output voltage available from the power amplifiers is ∼35 V(0-P), although for miniature ion traps, less than 5 V is commonly used. The same dc float potential applied to the ring electrode is applied to the end-cap electrodes so that no dc offset between the ring and end-cap electrodes is present. To perform tandem mass spectrometry experiments, ions are isolated using stored waveform inverse Fourier transform (SWIFT) waveforms,69 applied in a dipolar manner on the end caps, which (68) Cooks, R. G.; Rockwood, A. L. Rapid Commun. Mass Spectrom. 1991, 5, 83. (69) Guan, S.; Marshall, A. G. Int. J. Mass Spectrom. Ion Processes 1996, 157/ 158, 5-37.


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allows simultaneous excitation and ejection of all but the ions of interest from the CIT. Following ion isolation, a sinusoidal excitation waveform, corresponding in frequency to the secular frequency of the ion of interest, is applied to the end caps in a dipolar fashion. The amplitude of this waveform is such that the ions are excited axially, but insufficiently to be ejected from the CIT. If enough energy is deposited into the excited ions through collisions with the relatively high pressure of air present in the CIT, the selected ion will fragment. Additional stages of mass spectrometry can be performed through repetition of the isolation/ dissociation cycle. A sinusoidal resonance ejection waveform (700 kHz, βz ) 0.7, qz ) 0.808, 3.8 V(p-p) amplitude) is usually applied in the same manner across the end-cap electrodes during the mass scan to hasten ion ejection and improve resolution. Quadrupole Ion Guide rf Generation/Amplification. Operation of the quadrupole ion guide requires a second high voltage rf system. The amplification techniques used to produce this highvoltage rf are similar to those used to power the CIT. An rf power amplifier identical to that used for the CIT was used in this system for the first stage of amplification, but a separate tuned LC circuit was constructed to provide a second stage of amplification. The inductor of this circuit was based on a custom-wound solenoidtype transformer. Since the ion guide requires the use of two phases of the rf drive signal, two secondary windings must be used. The primary of the transformer is wound about a 38.1-mmouter diameter PVC tube from three turns of 20-gauge magnet wire. Two identical secondary windings are wound to either side of the primary winding, generating two amplified rf drive signals, 180 deg out of phase, with a maximum rf voltage of ∼400 V(0-P). A dc float potential can also be applied to the secondary windings to provide the proper dc bias for the ion guide relative to the rest of the ion optics. The sinusoidal rf drive signal for this system is provided through direct digital synthesis (DDS) of a sinusoidal waveform using an Analog Devices, Inc. (Norwood, MA) DDS chip. The chip (AD9833) is capable of generating sine, square, and triangle waveforms with 0.1-Hz resolution to 12.5 MHz at an output voltage of 500 mV(0-p). An evaluation board containing the DDS chip, a reference clock, and a computer interface port was used as purchased. The frequency of the generated waveform is controlled through the parallel port of the instrument control computer using software provided with the evaluation board. An adjustable-gain operational amplifier circuit was built in the prototyping area of the evaluation board to provide for the adjustment of the rf amplitude applied to the rods of the ion guide. This circuit provides a maximum output of 5 V(0-p) that is fed into the rf power amplifier described above. Tuning of the LC circuit is accomplished by adjusting the frequency applied to the amplifier until a resonance condition is achieved. Dc Power Supplies. A low-voltage dc power system was constructed from multiple dc-to-dc power supply modules to provide the numerous low-voltage dc levels necessary for the operation of the various electronics components of the instrument from the main 24-V input power supply. This system uses high power density converter modules (second generation modules, Vicor Corp., Andover, MA) to provide voltages of 5, 12, (24, and (39 V. A smaller (15 V dc-to-dc (BXA10-48D15, Artesyn Technologies, Milpitas, CA) module is also used. 2934


A high-voltage dc ion gating power supply was built utilizing a high-voltage dc-to-dc power supply (5VV1, Pico Electronics, Inc., Pelham, NY). The 1-kV supply is used to produce an ∼(450-V bipolar power supply using zener diodes. Ion gating is performed by placing a slightly negative voltage on the lens following the square quadrupole ion guide during ion injection and applying a high positive voltage on the lens to prevent ions from passing through the lens during mass analysis. An operational amplifier “switch” was designed to switch these voltages with the TTL level timing signal provided by the timing card included in the instrument control hardware. The dc bias on the ion optical elements is provided through the use of a nine-channel, (500-V bipolar power supply (TD9500HV, Spectrum Solutions Inc., Russellton, PA). A second (450-V bipolar power supply was constructed as described above to provide a much smaller ion optical element biasing supply, but was not used in these experiments. Detection System. A custom-designed Detector Technologies, Inc. (model 328, Palmer, MS) off-axis conversion dynode/electron multiplier assembly was used in this instrument. The detector assembly consists of a conversion dynode and miniature electron multiplier mounted within a shielded housing. This assembly was removed from its original mount and modified to fit within the vacuum manifold while still remaining within its shielded housing. A PEEK mount was machined to hold the ion entrance aperture of the detector in line with the CIT on the same alignment rods used to mount the ion optics of the third vacuum stage. The detector is biased using two high-voltage power supply modules (Spellman High Voltage Corp., Hauppauge, NY). One of these, a 1.5-W, 5-kV, reversible polarity supply (MM series) is used to bias the conversion dynode between 0 and (5 kV. The second, a low ripple, 3-W, -2.5-kV supply (MS series) is used to bias the electron multiplier between 0 and -2.5 kV. A current preamplifier from Keithley Instruments, Inc. (428-PROG, Cleveland, OH) is used to amplify the ion signal before digitization by the instrument control system. The preamplifier allows for a user selectable gain between 103 and 1011 V/A and a user-selectable rise time filter to reduce high-frequency noise. In the experiments described here, a gain of 107 V/A was chosen with a rise time filter of 10 µs to reduce the presence of high-frequency noise, while minimizing peak distortion that could result from the limited amplifier bandwidth. It is possible to increase the sensitivity of the instrument through the use of the higher gain settings on the preamplifier, but this comes at the expense of increasing peak width (decreasing resolution) through decreased bandwidth, as well as limiting the instrument’s dynamic range through overloading of the current amplifier. Ionization Sources. The initial characterization of this instrument has been performed using two general types of API sources, a corona discharge and two electrospray ionization sources. An enclosed corona discharge ionization source, shown in Figure 4, was constructed in a manner similar to one used previously in this laboratory.47 The source consists of a 1/4-in. (6.35-mm) Swagelok tee through which a Teflon insulated stainless steel wire is passed. A short length of 0.07-mm-diameter tungsten wire is spot welded to the end of the wire to form the discharge electrode. The wire is held in place at one end of the tee using a Teflon reducing ferrule, passed straight through the tee, and positioned

Figure 4. Illustration of the corona discharge ionization source constructed for the limit of detection studies. Gaseous samples enter the side port of the tee and are directed through holes in the PEEK electrode support piece into the atmospheric pressure ionization source chamber. A corona discharge is established by placing a high voltage on the discharge electrode relative to the inlet on the instrument.

at the other end in the center of a machined PEEK cylinder. Gaseous samples enter the tee through the third connection and are passed through an array of holes in the PEEK cylinder supporting the discharge tip. The corona discharge is contained within a volume created by an outer PEEK cylinder, which creates an atmospheric pressure chamber in which the gas composition can be controlled. A corona discharge is produced in a point-toplane geometry with respect to the stainless steel inlet capillary of the mass spectrometer when a high voltage is placed on the stainless steel wire. Typically, a voltage of 3.5 kV is placed on the wire using a (8-kV power supply (MS1007, K&M Electronics, Inc., West Springfield, MA). An electrospray ionization source and a nanospray ionization source were constructed to test the instrument using electrospray ionization. The electrospray source consists of a 60-cm-long fusedsilica capillary (Agilent Technologies, Inc., Palo Alto, CA) with an inner diameter of 0.100 mm and an outer diameter 0.190 mm, fixed using graphite ferrules inside a 1/16-in. (1.59-mm) Swagelok tee. The tee is held in position with respect to the inlet capillary of the instrument by a Delrin holder, placed on an XYZtranslational stage that allows one to adjust the position of the source relative to the stainless steel inlet capillary. Solutions containing the analytes used in these experiments were delivered through the fused-silica capillary using a syringe pump (model 22, Harvard Apparatus, Inc., Holliston, MA) at flow rates of between 1.0 and 5.0 µL/min. A typical bias of 3 kV was applied directly to the needle of the syringe using the same power supply used for the corona discharge source. The nanospray ionization source used commercially available static nanospray tips (ECONO 10, New Objective, Inc., Woburn, MA) held in a microelectrode holder (EH Series, Harvard Apparatus, Inc., Holliston, MA). The microelectrode holder allows the nanospray tip to be placed in the same Delrin holder as the electrospray and to be positioned using the same translational stage. A fine silver wire is used to make contact to the solution within the spray tip through the contact at the rear of the microelectrode holder. A typical bias of 2 kV is applied to the solution to produce the spray. Sample Preparation. Gas-phase standards were produced through the dilution of a saturated headspace sample of the compound of interest. Methyl salicylate and nitrobenzene were

obtained from Sigma-Aldrich Corp. (Milwaukee, WI) and used without further purification. A sample of ∼1 mL of the analyte of interest was placed into a sealed 1-L volumetric flask containing ambient air and maintained at 25 °C for 1 h to allow liquid-vapor equilibrium to be reached. The analyte concentration in the gaseous headspace solution was calculated based on the known vapor pressure of the analyte.70 Gas-phase standards were prepared by taking an aliquot of this gas mixture using a gastight syringe fitted with a shutoff valve (sample lock series, Hamilton Co., Reno, NV). The sample was injected at a controlled flow rate using a syringe pump into a diluent gas stream of grade D OSHA breathable air (BOC Gases, Murray Hill, NJ) flowing at approximately 500 or 1090 mL/min into the ionization source, as controlled using a mass flow controller (model HFC-302, Teledyne Hastings Instruments, Hampton, VA). All compounds used for electrospray ionization were obtained from Sigma-Aldrich and used without further purification. Solutions of the compounds used were prepared using HPLC grade solvents and deionized water. RESULTS AND DISCUSSION In the development of this instrument, an effort was made to minimize the size, weight, and power consumption of all components with the ultimate goal of producing a field-portable instrument. The completed instrument measures ∼46 × 50 × 38 cm, weighs ∼38 kg, and consumes 210 W while operating. The use of the rotary vane pump (15 × 47 × 24) adds 28 kg and 550 W to the package, but this is a temporary expedient. The packaging of the instrument has not been optimized to the smallest possible configuration, nor have the electronics been miniaturized to the smallest ultimate size, as the instrument has been designed to maximize flexibility in terms of both the software and hardware. This flexibility allows for the use of multiple types of ionization sources as well as the ability to add hardware and to perform future experiments of interest such as ion mobility spectrometry/ mass spectrometry. Many experiments were carried out to demonstrate the performance of the instrument using different API sources. The initial characterization focused on performance in ambient air monitoring using corona discharge ionization for applications such as chemical warfare agent and toxic industrial chemical monitoring. Additional experiments performed using electrospray ionization sources were intended to demonstrate and support further development of the capabilities of this instrument with other types of API sources. The data presented are typical data taken during this initial characterization. Corona Discharge Ionization. To investigate the instrument’s basic performance as a mass spectrometer, a corona discharge source was constructed. Various samples were introduced into the instrument to determine its mass resolution and mass/charge range. In these and all corona discharge ionization experiments described, the inlet capillary was held at room temperature. Figure 5a shows a typical mass spectrum of background air acquired using the low mass range conditions described in Table 1. The spectrum displays a wide distribution of protonated water clusters, (H2O)n H+, where n ranges from 3 to 23 with the maximum of (70) Daubert, T. E.; Danner, R. P. Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation; Hampshire Pub. Corp.: New York, 1989.


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Figure 6. (a) Mass spectrum the chemical warfare agent simulant methyl salicylate at 1.24 ppb in dry air using corona discharge ionization. (b) Mass spectrum of 12.4 ppb methyl salicylate in dry air.

Figure 5. Mass spectra of ambient air using corona discharge ionization under different instrument conditions. (a) Instrument optimized for lower mass/charge ions. A series of protonated water clusters (H2O)nH+ with n ) 3-23 is observed. (b) Instrument optimized higher mass/charge ions. A series of protonated water clusters (H2O)nH+ with n ) 8-25 is observed.

the distribution occurring at n ) 10. To efficiently trap ions of higher mass/charge ratio, the dc float potential on the ion trap must be slightly reduced (-2.5 to -1.7 V) to compensate for differences in the velocity of the higher mass ions. Figure 5b shows a distribution of water clusters recorded under high mass conditions, where n ranges from 8 to 25 with the maximum of the distribution occurring at n ) 15. The data shown in Figure 5a and b were acquired with no buffer gas present in the ion trap, i.e., operated at the instrument’s base pressure. The observation of a series of protonated water clusters has been made previously in our own work as well as that performed by others.46,47 Under typical operating conditions, a relatively high pressure of a buffer gas is used to improve the trapping efficiency of externally injected ions, increase CID efficiency, and improve mass/charge resolution. When operated with air as a buffer gas at 1 mTorr, the observed distribution of clusters narrows to cover only to the n ) 3-5 range, presumably due to CID during the ion trapping and cooling periods. The dissociation of the larger clusters when operated using buffer gas has the potential to improve performance as it removes much of the background seen in the corona discharge spectrum of ambient air. However, it may also have undesirable effects when recording signals from weakly bound or easily dissociated species. These data also show one important measure of instrument performance, the mass/charge range. From the water cluster data, the instrument displays a mass range up to ∼450 Th, with a low mass cutoff of ∼45 Th and a resolution at full scan speed (∼26 666 Th/s) of ∼250 (full width at halfmaximum, fwhm, definition). The value of the instrument in trace analysis was assessed by measuring the limits of detection for organic species present in 2936 Analytical Chemistry, Vol. 77, No. 9, May 1, 2005

Figure 7. (a) Partial mass spectrum showing the resolution, R ) m/∆m ) 255 (fwhm definition) for the 121 Th fragment ion of methyl salicylate from a 44 ppb sample in dry air. (b) Partial mass spectrum showing R ) 295 for the 153 Th ion of methyl salicylate from the same spectrum.

air using the corona discharge ionization source. Compounds selected for this investigation were the chemical warfare agent simulant methyl salicylate (C8H8O3, molecular weight 152.15) and the explosive analogue nitrobenzene (C6H5NO2, molecular weight 123.11). Gaseous samples of each compound were prepared as described above at concentrations ranging from approximately 100 pptr to 1 ppm (v/v) in the tank air. The samples were delivered directly into the enclosed ionization region located at the inlet of the mass spectrometer by the diluent gas flow. The limit of detection was taken as the concentration at which the intensity of the signal due to the analyte present in the air stream was equal to three times that of the noise. Figure 6a shows a mass spectrum at the limit of detection concentration of 1.24 ppb methyl salicylate in dry air. Due to the use of dry tank air as a diluent gas, the presence of water clusters in the observed spectra is suppressed without the need to heat the inlet capillary, although other chemical background is still present. The protonated molecule at 153 Th is seen in the data, as well as a low abundance characteristic fragment ion (121 Th) due to the loss of methanol from the protonated molecule. Figure 6b shows a mass spectrum obtained at 10 times the limit of detection, 12.4 ppb. The dynamic

Figure 8. (a) Mass spectrum of nitrobenzene at 629 pptr in dry air using corona discharge ionization. (b) Mass spectrum of 6.29 ppb nitrobenzene in dry air.

range of the instrument as given by the linear region of the calibration curve generated for methyl salicylate was just a factor of 20, stretching from the LOD to ∼24.7 ppb, the upper value being set by saturation of the current amplifier. A solution to the limited dynamic range is to implement an automatic gain control scheme to control and normalize the number of ions trapped in the CIT by varying the length of time the ions are passed into the CIT. Such approaches are successfully implemented in many commercial ion trap instruments. The resolution achievable by the CIT was investigated using the corona discharge ionization source with methyl salicylate as the sample and employing a reduced scan speed of 13 333 Th/s. The resolution of the instrument can be seen in the enlarged mass spectra shown in Figure 7. A resolution of ∼255 is observed for the 121 Th fragment using the fwhm definition, while that measured for the protonated molecule is 295. In both cases, the resolution corresponds to a fwhm value of ∼0.50 Th. Also seen

in the spectra are the nearly baseline resolved 13C isotope peaks. These mass spectra, as well as the other data presented in the article, are the average of 10 individual mass spectra to improve the signal-to-noise ratio. The rf circuitry designed for this, as well as the other miniature instruments developed in the laboratory, do not have rf feedback and stabilization of the CIT rf drive. As a result, small variations in the scan-to-scan rf voltage causes peak shifting, manifested in the averaged spectra as increased peak width and decreased resolution. It is expected that when feedback stabilization of the rf circuitry is complete, resolution approaching that seen in an identical CIT operated using a commercial, fullsized stabilized rf drive will be achieved.59 A second limit of detection study was performed using nitrobenzene in dry air. The limit of detection for nitrobenzene was determined to be 630 pptr. A mass spectrum recorded at this concentration is shown in Figure 8a. In the case of nitrobenzene, only the protonated molecule is formed (124 Th), the sensitivity being increased by the fact that the ion current is concentrated into a single ion. Data taken at a higher concentration sample, 6.30 ppb, is shown in Figure 8b. Although the lack of fragmentation can lead to simplified mass spectra when looking at complex mixtures, it also makes the accurate identification of unknown chemical species difficult. To solve this problem and in order to increase the specificity of the analysis, tandem mass spectrometric experiments were performed. Figure 9 demonstrates the performance of the miniature CIT in the MS/MS mode. A full scan mass spectrum of 6.54 ppb nitrobenzene in dry air with a small methyl salicylate background is shown in Figure 9a. Protonated nitrobenzene is isolated using a SWIFT isolation waveform (3.28-ms pulse, 10-1000-kHz bandwidth, 265-280-kHz notch, 4.56-V(p-p) amplitude) with a notch corresponding to the secular frequency of the nitrobenzene ion (273 kHz). The isolated peak is shown in Figure 9b, and it should be noted that unit mass isolation was achieved with 57% efficiency. Figure 9c shows the product ion MS/MS spectrum of nitrobenzene after effecting CID of the precursor ion

Figure 9. Sequence of mass spectra showing the tandem mass spectrometry capabilities of the instrument. (a) Full scan mass spectrum of 6.54 ppb nitrobenzene in dry air by corona discharge ionization (note methyl salicylate background at 121 and 153 Th), (b) unit m/z isolation of [nitrobenzene + H]+ precursor ion, and (c) product ion MS/MS spectrum of protonated nitrobenzene.


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capillary inlet was maintained at 40 °C to aid in the dissociation of these clusters. A solution of 100 µM arginine was introduced into the instrument at a flow rate of 5 µL/min, ionized by ESI, and the resulting mass spectrum is shown in Figure 10a. The spectrum shows the expected signal at 175 Th, corresponding to the [arginine + H]+ ion. A nanospray spectrum of the same solution is shown in Figure 10b, using the nanospray apparatus described above. The resolution of the instrument using electrospray ionization (R ) 350) is comparable to that seen in the corona discharge experiments, as shown in the inset of Figure 10a. Further demonstration of the capabilities of the instrument in the analysis with small drug molecules is shown in Figure 11. In this experiment, 10 µM solutions of (-)-ephedrine and lomefloxacin were electrosprayed at a flow rate of 3 µL/min and their ESI spectra are displayed in Figure 11a and b, respectively. The spectra show the generation of protonated molecules for each compound, consistent with the expected results. Figure 10. (a) Electrospray ionization mass spectrum of 100 µM (D,L)-arginine. Inset shows resolution of R ) 372 achieved for this sample. (b) Nanospray ionization mass spectrum of 100 µm (D,L)arginine displaying similar resolution.

by the application of a sinusoidal excitation waveform (273 kHz, 0.75-V(p-p) amplitude) + following the SWIFT isolation. The CID efficiency, calculated as the sum of the peak heights for the product ions divided by the peak height for the precursor ion, was ∼94% in this experiment. Again, the linear dynamic range of the instrument during the single-stage mass spectrometry experiments was limited, this time to 2 orders of magnitude, due to saturation of the current amplifier at concentrations above ∼100 ppb. Electrospray Ionization. To demonstrate the capabilities of this instrument with electrospray ionization, both electrospray and nanospray ionization sources were tested. Solutions of (D,L)arginine (C6H14N4O2, molecular weight 174.2), (-)-ephedrine (C10H15NO, molecular weight 165.23), and lomefloxacin (C17H19F2N3O3, molecular weight 351.8) were prepared in 49:49:2 methanol/ water/acetic acid at concentrations of 10-1000 µM. Because of the ease of generation of solvated ions by electrospray, the

CONCLUSION A miniature mass spectrometer based on a miniature CIT mass analyzer with an atmospheric interface has been built and characterized. The instrument has been used to analyze ions generated by corona discharge ionization as well as by electrospray ionization. The ability to implement multiple types of API sources enables the user to select ionization techniques appropriate to particular samples and to improve the sensitivity and specificity toward selected analytes. The initial characterization of the instrument has shown a mass/charge range of ∼450 Th through the generation of protonated water clusters from humid air. Limits of detection for the determination of the chemical warfare agent simulant methyl salicylate and nitrobenzene from dry tank air were determined to be 1.24 ppb and 630 pptr, respectively. Currently, the instrument has a limited dynamic range when operated using the same experimental conditions (ionization time and current amplifier gain) to analyze samples over a wide range of concentrations. The instrument displays unit mass resolution throughout the mass/charge range, with peak widths ranging from ∼0.5 Th at low masses up to ∼1 Th at higher masses. The instrument has also been successfully

Figure 11. (a) Electrospray ionization mass spectrum of 10 µM (-)-ephedrine. (b) Electrospray ionization mass spectrum of 10-µm lomefloxacin. 2938


demonstrated using electrospray ionization sources with a variety of compounds. Further development of this instrument will include additional reduction in overall size, weight, and power consumption through improvements in many components. Emphasis will be placed on reducing the size and weight of the vacuum system with the elimination of the rotary vane pump currently used for the evacuation of the first vacuum stage. To reach this goal, new vacuum pump technology will be used, together with reduction in the gas flow rates between vacuum stages via the use of smaller apertures. In addition, line-of-sight molecular transfer though the capillary/skimmer region will be eliminated by placing the capillary off-axis with respect to the skimmer, preventing the transmission of large charged droplets and reducing the gas load on the next vacuum stage. It is essential that any compromises made to meet the goals of future versions of this instrument do not reduce its performance. The replacement of the CIT with a higher performance rectilinear ion trap,71 a new mass analyzer with improved trapping efficiency and ion storage capacity, will be performed in a effort to improve performance. Finally, the ion optics will be redesigned to remove the mass discrimination seen (71) Ouyang, Z.; Wu, G.; Song, Y.; Li, H.; Plass, W. R.; Cooks, R. G. Anal. Chem. 2004, 76, 4595-4605.

in trapping high mass ions through the replacement of the einzel lens with an additional rf-only ion guide. ACKNOWLEDGMENT The authors acknowledge the primary funding for the development of this instrument from ONNAVSEA/NSWC Crane N0016400-C-0047 through the Integrated Detection of Hazardous Materials (IDHM) program. Additional funding was received from NASA’s Jet Propulsion Laboratory under the Planetary Instrument Definition and Development Program (PIDDP), and the Astrobiology Science and Technology Instrument Development (ASTID) program. B.C.L. acknowledges the Phillips Petroleum Company for fellowship support. C.C.M. acknowledges fellowship support from the Department of Education Graduate Assistantships in Areas of National Need (GAANN) program. The authors also thank Andrew Guymon, Jason Duncan, Greg Hawkins, and Randy Replogle of the Jonathan Amy Facility for Chemical Instrumentation for their roles in the construction and continued support of this instrumentation. Received for review December 12, 2004. Accepted March 1, 2005. AC0481708


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Atmospheric Pressure Ionization in a Miniature Mass Spectrometer

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