Analytical Performance of a Miniature Cylindrical Ion Trap Mass

Anal. Chem. 2002, 74, 6154-6162

Articles

Analytical Performance of a Miniature Cylindrical Ion Trap Mass Spectrometer Leah S. Riter, Yanan Peng, Robert J. Noll, Garth E. Patterson,† Tenna Aggerholm, and R. Graham Cooks*

Chemistry Department, Purdue University, West Lafayette, Indiana 47907

The analytical performance of a fieldable cylindrical ion trap (CIT)-based miniature mass spectrometer is described. A detailed description of the instrument itself is to be found in the immediately preceding paper (Patterson, G. E.; Guymon, A. J.; Riter, L. S.; Everly, M.; GriepRaming, J.; Laughlin, B. C.; Ouyang, Z.; Cooks, R. G., Miniature Cylindrical Ion Trap Mass Spectrometer, Anal. Chem. 2002, 24, 6145-6153). Applications employing the MS/MS and MSn capabilities of the miniature instrument and analytical performance criteria are given here. The limit of detection for methyl salicylate, introduced as the pure vapor, is estimated as 1 pg. The resolution, R ) m/∆m, where ∆m, measured as full width at halfmaximum, is estimated as 100. Monitoring of organic compounds in air is performed using a permeation membrane introduction device coupled to the mass spectrometer. Water monitoring is performed using an external membrane introduction mass spectrometry (MIMS) system, with acetophenone and toluene serving as model compounds. Data are given for chemical warfare agent simulants, methyl salicylate, and dimethyl methyl phosphonate (DMMP) in air. On-line detection of menthol vapor emitted from a cough drop is reported. Methyl salicylate in air gives a recognizable mass spectrum at 400 ppb in the ambient system, while use of a heated membrane brings the detection limit down to 10 ppb. The purpose of this paper is to describe the analytical performance of a fieldable cylindrical ion trap (CIT)-based miniature mass spectrometer, described in the accompanying instrument paper.1 Analytical performance criteria, including sensitivity and resolution, are presented, as are applications that employ MS/MS and MS/MS/MS spectra. One motivation for developing such instrumentation is the detection of chemical warfare (CW) agents, a problem in trace organic analysis of great challenge and importance. Necessary performance criteria for an analytical system appropriate to this problem include (i) high † Purdue University and Griffin Analytical Technologies, Inc. West Lafayette, IN 47906. * Fax: 765-494-9421. E-mail: [email protected]. (1) 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, 24, 61456153.

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speed of analysis, (ii) low detection and quantitation limits, (iii) high specificity in detection of target compounds, (iv) good precision and accuracy, and (v) an instrument that is lightweight, compact, and can be operated on battery power for extended periods. These formidable demands must be accomplished by a system capable of continuous operation in real-time and in situ. Analysis for CW agents requires detection in complex mixtures (e.g., in air that also contains complex mixtures of compounds, such as those present naturally, as well as those found in vehicle exhaust and other anthropogenic sources). Successful analysis of CW agents in complex mixtures depends on (i) achieving selectivity toward the analytes of interest and (ii) discriminating against possible interfering agents while (iii) maintaining maximum signal/noise ratios. These capabilities need to be achieved to such an extent as to make the system highly reliable in producing a response to analytes while eliminating false positives. One way to achieve the necessary sensitivity and selectivity is to use a sequence of operations performed in series. This conceptual approach to complex mixture analysis is adopted in the applications of the miniature tandem mass spectrometer described here. The sequence of operations used includes sample introduction, selective preconcentration/separation via membrane introduction mass spectrometry,2 selective ionization, mass selection, collisioninduced dissociation, a second stage of mass analysis, and finally, signal detection. The Paul ion trap3 is an especially appealing instrumental platform for miniaturization because it offers advantages that include high sensitivity, the ability to operate at higher pressures (∼10-3 Torr) than other types of mass spectrometers,4 and the ability to perform multiple stages of mass analysis5-7 in a single analyzer device. (2) Johnson, R. C.; Cooks, R. G.; Allen, T. M.; Cisper, M. E.; Hemberger, P. H. Mass Spectrom. Rev. 2000, 19, 1-37. (3) March, R. J. Mass Spectrom. 1997, 32, 351-369. (4) 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. (5) McLuckey, S. A.; Glish, G. L.; VanBerkel, G. J. Int. J. Mass Spectrom. Ion Processes 1991, 106, 213-235. (6) Louris, J. N.; Cooks, R. G.; Syka, J. E. P.; Kelley, P. E.; Stafford, G. C.; Todd, J. F. J. Anal. Chem. 1987, 59, 1677-1685. (7) Johnson, J. V.; Yost, R. A.; Kelley, P. E.; Bradford, D. C. Anal. Chem. 1990, 62, 2162. 10.1021/ac0204956 CCC: $22.00

© 2002 American Chemical Society Published on Web 11/09/2002

The cylindrical ion trap (CIT) has long been known to function as a three-dimensional ion storage device,8 although its use as a mass analyzer is much more recent.9 Near the center of the device, the fields are quadratic in both the radial and axial directions, although at greater distances from the center, the approximation to a true Paul trap becomes far less accurate.9,10 The full-size CIT mass analyzer provides similar performance, especially at mass/ charge ratios below 500 Thomson (Th),11 to a conventional hyperbolic ion trap.9 Because of the simplified electrode design, typically consisting merely of flat endcaps and a cylindrical ring electrode, CITs are much easier to machine than hyperbolic ion traps and can therefore be miniaturized more readily. For these reasons, considerable recent work has focused on the miniaturization of CIT10,12,13 mass analyzers. Smaller ion traps require significantly lower voltages and less power than larger traps, allowing simplification and miniaturization of the instrumental electronics. On the other hand, analytical performance of the CIT is expected to be affected adversely by miniaturization. As the volume of the ion trap decreases, the number of ions that can be stored decreases (this problem can be alleviated by using arrays of traps, as discussed below). Decreased rf voltage reduces the mass range of the analyzer; however, with miniaturization, the required rf voltage also decreases. The use of multiple traps in a parallel array, first done in the case of linear quadrupoles,14 can offset the loss in chargecarrying capacity upon miniaturization. A mass/charge range of up to 600 Th and unit resolution has been achieved in devices with internal radius (r0) of just a few millimeters.9 Several groups have investigated the performance of miniature ion trap mass analyzers. The first miniature quadrupole ion trap (QIT) was built in a collaborative project between this laboratory at Purdue University and Los Alamos National Laboratory.15 Halfand quarter-sized (5.0- and 2.5-mm inner radius) ion traps were constructed to extend the mass-to-charge range, and ions up to 70 000 Th were observed, although with poor mass resolution. Because of the demanding machining requirements of the hyperbolic surfaces, ion traps with this geometry are difficult to reduce in size any further. Prototype CITs with r0 of 5.0 and 2.5 mm have been successfully demonstrated in this laboratory,10 Ramsey et al.12 have reported on CITs with r0 ) 0.5, 1.0, and 2.0 mm, and Lynn and co-workers16 have reported data on CITs with r0 ) 3.2 mm. Fourier transform nondestructive detection, using a small pin electrode embedded in but electrically isolated from the exit endcap electrode, has been demonstrated for cylindrical ion traps.17 The fields in CITs have been carefully optimized18 through (8) Langmuir, D. B.; Langmuir, R. V.; Shelton, H.; Wuerker, R. F. Containment Device. U.S. Patent 3,065,640, 1962. (9) Wells, J. M.; Badman, E. R.; Cooks, R. G. Anal. Chem. 1998, 70, 438-444. (10) Badman, E. R.; Johnson, R. C.; Plass, W. R.; Cooks, R. G. Anal. Chem. 1998, 70, 4896-4901. (11) Cooks, R. G.; Rockwood, A. L. Rapid Commun. Mass Spectrom. 1991, 5, 93. (12) Kornienko, O.; Reilly, P. T. A.; Whitten, W. B.; Ramsey, J. M. Rapid Commun. Mass Spectrom. 1999, 13, 50-53. (13) Kornienko, O.; Reilly, P.; Whitten, W.; Ramsey, M. Rev. Sci. Instrum. 1999, 70, 3907-3909. (14) Ferran, R. J.; Boumsellek, S. J. Vac. Sci. Technol., A 1996, 14, 1258-1265. (15) 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. (16) Meaker, T. F.; Lynn, B. C. In Tandem Mass Spectrometry in a Miniature Cylindrical Ion Trap, Proceedings of the 49th ASMS Conference on Mass Spectrometry and Allied Topics, Chicago, IL, 2001.

systematic variation in such parameters as the center-to-endcap distance z0, ring electrode thickness zb, endcap hole radius rhole, and the spacing d between the ring electrode and the endcap.10 The stochastic multiple-particle simulation program ITSIM 19-21 has been adapted to allow comparison of performance in simulations and experiments. The Ramsey group has coupled reduced size CITs (r0 ) 0.5-2.0 mm) with ion sources that use laser ionization,12 electron ionization,13 and field-emission cold-cathode electron ionization.22 Ramsey has also studied ion ejection processes from miniature CITs by resonance excitation to increase ion signal intensity and resolution.23 The MSn (n ) 2, 3) capabilities of full-sized CITs have been demonstrated in our earlier work9 and those of reduced-size devices in the work of Lynn.16 Because a decrease in ion trap size results in a shallower pseudopotential ion trapping well, tandem mass spectrometry becomes less efficient as trap size is decreased. Nonetheless, Lynn and co-workers have reported tandem mass analysis (MS/MS) of acetophenone in a miniature CIT (r0 ) 3.2 mm).16 The geometrical simplicity of miniature CITs lends itself to the design of ion trap arrays. Three different types of CIT arrays have been demonstrated: (i) variable r0 parallel arrays (in which the value of r0 for a particular element in the array determines the mass-to-charge ratio of the ions trapped in that element);24 (ii) single r0 parallel arrays (multiple traps of the same dimensions arranged in parallel and operated using the same applied voltages), which can be used to increase trapping capacity and hence signal strength25; and (iii) serial arrays (traps with single r0, arranged in series)26 used to add the capability to perform MS/MS experiments in space. The focus of this study is on performance of a miniature mass spectrometer that contains a small (2.5-mm radius) CIT mass analyzer. The small size of the overall instrument is important in meeting the design and performance requirements laid out above. EXPERIMENTAL SECTION A miniature mass spectrometer, based on a CIT mass analyzer, has been designed and constructed. It is more completely described in the immediately preceding paper.1 The CIT (r0 ) 2.5 mm, z0 ) 2.7 mm) is operated with an rf drive frequency of 2 MHz and a maximum voltage of 1000 V(0-P). The resulting upper mass/charge limit of the instrument under these operating conditions is ∼250 Th. Electrons generated by thermionic emission from a rhenium filament (emission current, 50 µA) are directed into the trap using a -13 V repeller potential. Upon (17) Badman, E. R.; Wells, J. M.; Bui, H. A.; Cooks, R. G. Anal. Chem. 1998, 70, 3545-3547. (18) Wu, G.; Zheng, O.; Plass, W. R.; Cooks, R. G. In Geometry Optimization of the Cylindrical Ion Trap, 50th Annual Conference on Mass Spectrometry and Allied Topics, June 2-6, 2002, Orlando, FL, 2002. (19) Reiser, H. P.; Julian, R. K.; Cooks, R. G. Int. J. Mass Spectrom. Ion Processes 1992, 121, 49-63. (20) Julian, R. K.; Reiser, H. P.; Cooks, R. G. Int. J. Mass Spectrom. Ion Processes 1993, 123, 85-96. (21) Bui, H. A.; Cooks, R. G. J. Mass Spectrom. 1998, 33, 297-304. (22) Kornienko, O.; Reilly, P. T. A.; Whitten, W. B.; Ramsey, J. M. Anal. Chem. 2000, 72, 559-562. (23) Moxom, J.; Reilly, P. T. A.; Whitten, W. B.; Ramsey, J. M. Rapid Commun. Mass Spectrom. 2002, 16, 755-760. (24) Badman, E. R.; Cooks, R. G. Anal. Chem. 2000, 72, 5079-5086. (25) Badman, E. R.; Cooks, R. G., Anal. Chem. 2000, 72, 3291-3297. (26) Ouyang, Z.; Badman, E. R.; Cooks, R. G. Rapid Commun. Mass Spectrom. 1999, 13, 2444-2449.

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entering the trap, electrons take up kinetic energy from the rf field and ionize neutral molecules. The resulting ions are trapped, mass selected, and manipulated using the normal ion trap operations available in instruments capable of resonance ejection and excitation. These capabilities allow tandem and higher-stage mass spectrometry experiments. Resonant ejection from the CIT is performed at qz ) 0.7, νeject ) 700 kHz, while ion detection is by an external channeltron electron multiplier (gain ) 106, model 7505MH1, K & M Electronics, Springfield, MA). The detector signal is amplified (107 gain, Keithley 427 current amplifier) then collected using an embedded PC-based data acquisition system. The system consists of a Pentium III 800 MHz ATX computer, a National Instruments 6070E multifunctional I/O card, a National Instruments 6602 timer card, and two arbitrary waveform generator cards (National Instruments, model 5411), all controlled with software written in-house (National Instruments, LabView Version 6.01). One arbitrary waveform generator is used to modulate the rf drive applied to the ring electrode, while the other supplies the axial modulation waveforms to the CIT endcap electrodes. Power for the computer, electronics, and vacuum pumps is provided by an uninterruptible power supply that provides both 24 V DC and 110 V AC outputs. Dimethyl methylphosphonate (DMMP), p-nitrotoluene, acetophenone, and methyl salicylate were obtained from Sigma-Aldrich (Milwaukee, WI) and were normally introduced as headspace vapors at ambient temperature from the neat liquids or solids using a variable leak valve (Granville-Phillips, series 203). Three freeze-pump-thaw cycles were used before sample introduction into the vacuum chamber. Reagent partial pressures were typically 4 × 10-6 Torr (uncorrected, model 354 Bayard-Alpert ion gauge, Granville-Phillips, Boulder, CO). In other experiments, organic compounds in air and water were sampled using the membrane introduction systems described below. Conditions for the limit of detection measurements are described in the appropriate section, below. Cough drops (Warner-Lambert, Morris Plains, NJ, “Ice Blue” flavor, 12 mg menthol/drop) were purchased at a local drug store. Gaseous standards were prepared using a gas dilution apparatus, described elsewhere.27 MS and MSn Conditions. For single-stage MS experiments, the scan function employed had four periods: a 5-ms delay period, 30-ms ionization time (electrons gated into trap to ionize neutral vapors), 15-30-ms ion cooling period, and a 15-ms analysis period.3 In the MSn experiments, the first two periods were immediately followed by an isolation period of 4 ms. During this period, isolation of the ions of interest was performed using the stored waveform inverse Fourier transform (SWIFT) method.28 SWIFT waveforms were calculated using the ion trap simulation program ITSIM, Version 5.0.29,30 Isolation conditions were optimized during each experiment to yield maximum signals for the ions of interest (4-ms SWIFT pulse, center frequency ranging from 250 to 390 kHz, with a 10-30 kHz bandwidth, amplitude 0.03 to 0.05V). This was followed by a period of 51 ms for collisional (27) Riter, L. S.; Takats, Z.; Cooks, R. G. Analyst 2001, 126, 1980-1984. (28) Guan, S.; Marshall, A. G. Int. J. Mass Spectrom. Ion Processes 1996, 157/ 158, 5-37. (29) Plass, W. R. Ph.D. Thesis, Ph.D. Thesis, Justus-Liebig-Universitaet, 2000. (30) Plass, W. R.; Cooks, R. G.; Goeringer, D. E.; McLuckey, S. A. Simulation of Ion Internal Energy Evolution During Collisional Processes in Quadrupole Ion Traps, 47th ASMS Conference on Mass Spectrometry and Allied Topics, Dallas, 1999.

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activation, achieved by applying a sine wave with a frequency chosen to match the secular frequency(ies) of the ion(s) of interest. The amplitude of this excitation waveform was chosen within the range 0.002-0.05 V, such that ions of interest would gain enough velocity to undergo energetic collisions with background gas (9.5 × 10-5 to 2.8 × 10-4 Torr, corrected ion gauge reading) but have insufficient energy to be immediately ejected from the trap. Product ions resulting from collision-induced dissociation (CID) were recorded in a mass-selective instability scan. In cases where MS/MS/MS experiments were recorded, a second sequence of isolation/cooling/activation steps was inserted before the mass analysis scan. The amplitude of the applied waveforms was varied in each experiment to optimize the efficiency of isolation and the degree of dissociation. Air Analysis Using Membrane Introduction. A miniaturized internal membrane inlet system was designed on a scale suited to the miniature mass spectrometer. It was intended to reproduce many of the features of a direct insertion membrane probe (DIMP).31 The membrane is positioned within the vacuum system and close to the electrode structure for maximum efficiency in transporting neutral analyte molecules into the ion trap for internal ionization. This new miniature MIMS system, shown in Figure 1A, was fabricated from two stainless steel tubes (1.65-mm o.d., 1.0-mm i.d., 8-cm total length, 2-cm length exposed to vacuum), inserted through holes (6 mm apart) drilled into a QF25 blank stub (MDC Vacuum Products, Hayward, CA) and welded in place. A loop of cross-linked poly(dimethylsiloxane) (Dow-Corning, 4 cm long, 0.64 mm i.d., 1.19 mm o.d.) connected the two stainless steel tubes inside the vacuum side, with a 2 cm length of membrane exposed to vacuum (0.75 cm3 total surface area). A diaphragm pump (gas flow rate 4 L/min, KNF Neuberger UNMP 50) was used to transfer external air through the stainless steel tubing and the PDMS membrane before being vented to atmosphere. Compounds that permeate the walls of the membrane enter the vacuum manifold and may pass into the CIT analyzer, where they may be ionized and analyzed. The membrane system, along with the entire mass spectrometer, was held at ambient temperature for these experiments, except for a series of experiments with a newer version of the instrument, which are specifically indicated. Improved performance is expected32 and observed when the temperature is raised, but this requires additional power, a premium commodity in a fieldable instrument. Ion trap pressures were nominally 2.0 × 10-5 Torr before sensitivity correction of the Bayard-Alpert ion gauge reading. Aqueous Solution Analysis by MIMS. A second MIMS system (Figure 1B), located externally to the mass spectrometer and fully described elsewhere33 was coupled to the mass spectrometer via a Swagelok vacuum feedthrough (Solon, OH). Crosslinked PDMS (3.5-cm-long tube, 0.64-mm i.d. and 1.19-mm o.d.) was used as the permeation membrane. Aqueous samples were passed through the membrane (flow rate 1 mL/min) while He flowed in the countercurrent direction in the annular region between the membrane and a PTFE tube jacket. The helium was (31) Bier, M. E.; Kotiaho, T.; Cooks, R. G. Anal. Chim. Acta 1990, 231, 175190. (32) Ketola, R. A.; Kotiaho, T.; Cisper, M. E.; Allen, T. M. J. Mass Spectrom. 2002, 37, 457-476. (33) Riter, L. S.; Charles, L.; Cooks, R. G. Rapid Commun. Mass Spectrom. 2001, 15, 2290-2295.

Table 1. Single-Stage MS, MS/MS and MS/MS/MS Spectra of p-Nitrotoluene, Acetophenone, Methyl Salicylate, and DMMPa MS/MS compd p-nitrotoluene

acetophenone methyl salicylate DMMP

b

MS/MS/MS

MSb

isolationb

dissociationc

isolationc

dissociationc

137 (4.8) 121 (1.1) 107 (1.4) 91 (1.2) 120 (1.3) 105 (2.0) 77 (1.2) 152 (1.4) 120 (0.9) 92 (0.7) 124 (1.0) 109 (0.2) 94 (0.4) 79 (0.8)

137 (4.6) 121 (0.4)

121 (2.0) 107 (0.2) 91 (0.3)

121 (0.5)

121 (0.5) 107 (0.08) 91 (0.1)

120 (1.0) 105 (0.2)

120 (0.4) 105 (0.7) 77 (0.06) 152 (0.2) 120 (0.7) 92 (0.1) 124 (0.7) 94 (0.1) 79 (0.5)

105 (0.6)

105 (0.4) 77 (0.06)

152 (1.1) 124 (1.7) c 79 (0.2)

152 (0.06) 120 (0.6) N/A

N/A N/A

a All data refer to pure samples of the compounds. In all cases, data are given as mass/charge ratio with peak heights (volts) in parentheses. No bath/collision gas. c He used as bath/collision gas.

Figure 1. Miniature membrane inlet systems designed to fit the miniature mass spectrometer: (a) internal MIMS system, used for air analysis; (b) external MIMS system, used for water analysis. Both systems used poly(dimethylsiloxane) membrane in a tubular configuration.

RESULTS AND DISCUSSION Results of representative experiments are listed in Table 1. For each column, observed mass-to-charge ratios are followed in parentheses by peak heights in volts. Peak heights are used instead of relative ion abundances so that absolute performance can be judged. Listed in the first column of Table 1 are the data recorded using single-stage mass spectrometry experiments. Other data in the Table is discussed in turn. The single-stage mass spectra acquired using the miniature CIT mass spectrometer are generally consistent with published ion trap mass spectra, although it must be emphasized that operating conditions have very large effects on ion trap mass spectra. Energy deposition and, hence, degree of fragmentation varies with conditions and ion/molecule reactions, charge exchange especially is also strongly condition-dependent. Besides this, the longer ion lifetimes and multiple low-energy collisions that occur in ion traps add to the sensitivity of the mass spectra of operating parameters. It is, therefore, expected that spectra will not necessarily match published standard spectra recorded using sector and quadrupole mass spectrometers. The major peaks observed in the mass spectra of p-nitrotoluene acquired in the miniature CIT mass spectrometer are also present in the NIST spectrum, at roughly the same relative intensities.35 Similarly, the molecular ion (137 Th) and 91 Th are the major peaks in the miniature CIT and the NIST mass spectra of p-nitrotoluene. Pronounced differences occur in the case of p-nitrotoluene where the relative abundance of the ion 121 Th is much greater in the mini-CIT as compared to the NIST spectrum (23% mini-CIT, 2% NIST). The effects are not due to the small size of the present trap, since large differences from the NIST spectra are observed in full-size traps, such as the commercial ITS-40 instrument in this case; moreover, changes in trap operating conditions with the large or small trap dramatically change the mass spectrum. Both the NIST and mini CIT spectra for acetophenone show three

used to sweep the permeate analyte from the MIMS interface to the mass spectrometer.34

(34) Slivon, L. E.; Bauer, M. R.; Ho, J. S.; Budde, W. L. Anal. Chem. 1991, 63, 1335-1340. (35) Stein, S. E. IR and Mass Spectra; Linstrom, P. J., Mallard, W. G., Eds.; National Institute of Standards and Technology: Gaithersburg, MD, July 2001; Vol. 69.


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major peaks at 120, 105, and 77 Th, with 105 Th as the base peak. For methyl salicylate, the mini-CIT and the NIST mass spectra show the same major peaks at 92, 120, and 152 Th; however, in the mini-CIT mass spectrum, the base peak is the molecular ion (152 Th), and the base peak in the NIST spectrum is the 120 Th fragment ion. Dimethyl methyl phosphonate (DMMP) is an important precursor and an impurity in G nerve agents (cholinesterase inhibitors) of the organophosphate family, including Tabun (GA), Sarin (GB), Soman (GD), and VX. It is a widely used simulant for phosphorus ester CW agents and has been examined previously using full-size ion trap mass spectrometers that used MIMS to sample DMMP from air.36 Cisper and Hemberger37 have previously published ion trap DMMP mass spectra that show effects of ion/molecule reactions. In an electrospray ionization ion trap experiment, collision-induced dissociation of protonated DMMP was shown to result in formaldehyde elimination with partial scrambling of the methyl groups attached to phosphorus and oxygen.38 The mass spectrum of DMMP recorded using the miniCIT shows the same ions as those reported in the NIST collection. However, the base peak in the mini-CIT spectrum was the molecular ion (124 Th) in the absence of helium bath gas, whereas it was the fragment at 109 Th in the presence of helium, and the ion of 94 Th ion is the base peak in the NIST spectrum. The present mini-CIT spectra quite closely resemble those recorded previously by Riter et al., in a commercial ion trap mass spectrometer.27 The second and third columns of Table 1 contain results for MS/MS experiments. The column labeled MS/MS isolation lists the peak heights of ions analyzed after application of the SWIFT pulse but before performing the ion activation step that leads to CID. This experiment is useful in gauging the efficiency achieved in isolating the ion of interest. Perfect isolation of an ion would be indicated by (i) the same ion peak height in both the MS/MS isolation column and in the single-stage MS column, indicating that no parent ions were ejected or otherwise lost during isolation; and (ii) by zero intensity of all other peaks in the MS/MS isolation column, indicating perfect removal of all other ions. Isolation efficiencies depend on resolution, and in these experiments sufficient resolution was used to avoid residual ion abundance from adjacent ions in the MS/MS spectra. The isolation efficiencies and percent residual ion abundance (the percent of the total ion peak height that comes from ions other than that being isolated) are typified by the cases of the molecular ions of methyl salicylate, p-nitrotoluene, and acetophenone. In the case of methyl salicylate, using 0.04 V ac amplitude at 240-260 kHz for 4 ms isolation time, the efficiency was 78%, and the isolation spectrum showed no residual ion abundance. In the case of acetophenone, isolation was performed using 0.04 V amplitude, 310-340 kHz, and 4 ms, the efficiency was 77%. However, in this case, 20% residual ion abundance due to ions of 105 Th is observed, this fragment being formed as the result of postisolation dissociation, as discussed further below. With p-nitrotoluene using 0.04 V amplitude, 270(36) Gordon, S. M.; Kenny, P. J.; Pleil, J. D. Rapid Commun. Mass Spectrom. 1996, 10, 1038-1046. (37) Cisper, M. E.; Hemberger, P. H. Rapid Commun. Mass Spectrom. 1997, 11, 1449-1453. (38) Barr, J. D.; Bell, A. J.; Konn, D. O.; Murrell, J.; Timperley, C. M.; Waters, M. J.; Watts, P. Phys. Chem. Chem. Phys. 2002, 4, 2200-2205.

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300 kHz, and 4 ms isolation time, the efficiency was 96%; there was 8% residual ion abundance in this case. The third column of Table 1, labeled MS/MS dissociation, presents conventional product ion MS/MS spectra. Criteria used to judge performance in this experiment are the attenuation of the molecular ion signal and the corresponding increase in the relative abundance of the fragment ions. Ideally, the total ion signal should remain constant before and after dissociation.The attenuation of the molecular ion peak heights of each compound (due to dissociation of the isolated molecular ion and scattering losses) and total ion conservation were acetophenone, 60% attenuation of molecular ion with total ion signal 97% of original (0.02 V amplitude, 320 kHz, 51 ms); methyl salicylate, 82% attenuation of the molecular ion with total ion signal 91% (0.02 V amplitude, 250 kHz, 451 ms); dimethyl methylphosphonate, 59% attenuation of the molecular ion with total ion signal 76% (0.015 V amplitude, 335 kHz, 51 ms); and p-nitrotoluene, 56% attenuation of the molecular ion with total ion signal 50% (0.05 V amplitude, 270 kHz, 51 ms). The fourth and fifth columns of Table 1 list data for MS/MS/ MS experiments. The second isolation step (after application of the SWIFT isolation pulse, but without CID) is recorded in column 4 of Table 1. As with the first isolation step in column 2, the criterion for performance is retention of signal due to the desired ion with zero intensity of all other ions. The results are pnitrotoluene (121 Th), 25% efficient with 0% residual ion abundance (0.05 V amplitude, 300-330 kHz, 4 ms); methyl salicylate (120 Th), 86% efficient with 10% residual ion abundance (0.04 V amplitude, 330-360 kHz, 4 ms); and acetophenone (105 Th), 85% efficient with 0% residual ion abundance (0.05 V amplitude, 380400 kHz, 4 ms). It is clear that there are chemcially dependent differences in isolation efficiency under the chosen conditions. The fifth column of Table 1, labeled MS/MS/MS dissociation, summarizes the conventional product ion MS/MS/MS spectra. As with column 3, the criteria used for performance evaluation are attenuation of the isolated ion abundance and retention of total ion signal. The isolated p-nitrotoluene fragment ion (121 Th), showed no detectable attenuation upon gentle collisional activation (0.003 V amplitude, 300 kHz, 51 ms); however, small signals due to the fragment ions 107 (0.08 V) and 91 (0.1 V) were detectable. Activation under more energetic conditions caused ejection of the parent ion from the trap because of the shallow pseudopotential well needed in order to perform the MS3 experiment. In the MS3 experiment on acetophenone, subsequent activation of the 105 Th ion (0.002 V amplitude, 390 kHz, 51 ms) caused 33% attenuation of the isolated ion signal with 77% retention of total ion current and formation of the fragment ion 77 Th in low abundance (0.06 V). As an example of the MSn experiments performed, the sequence of mass scans recorded in the course of obtaining the MS/MS/MS sequential product spectrum of p-nitrotoluene are depicted in Figure 2. In Figure 2A, the single-stage mass spectrum is reproduced; it includes the molecular ion 137 Th and fragment ions at 121, 107, and 91 Th. The conditions under which this spectrum was recorded were chosen to maximize the number of ions; there is, therefore, a noticeable loss of resolution due to space charge. Figure 2B shows the isolation of the molecular ion by application of a SWIFT waveform (0.04 V amplitude, 270-300 kHz,

Figure 2. p-Nitrotoluene data showing (A) single-stage mass spectrum; (B) isolation of the molecular ion by application of a SWIFT waveform (0.04 V amplitude, 270-300 kHz, 4 ms); note that all ions at 107 and 91 were ejected, while the abundance of ions of 121 Th is attenuated to 10% of the total signal; (C) application of activation signal (0.05 V amplitude, 270 kHz, 51 ms) to cause CID of ions of 137 Th and produce the observed collection of product ions; (D) isolation (0.05 V amplitude, 300-330 kHz, 4 ms) of the secondgeneration fragment ion, 121 Th, (note that all of the unwanted ions are ejected from the trap; however, this comes at the expense of a drop in peak height for the ion of interest); and (E) activation of 121 Th (using a resonance excitation signal of 0.003 V amplitude, 300 kHz, 51 ms) and collection of third-generation ions at 107 and 91 Th.

4 ms). Note that all ions at 107 and 91 Th were ejected, while the abundance of 121 Th was attenuated to the point where its peak height was only 10% of the original value. As is usual in multistage MS experiments, the conditions were chosen as a compromise between isolation efficiency and isolated ion purity in order to retain enough ion signal for all stages of mass analysis. Figure 2C shows the result of application of CID activation (0.05 V amplitude, 270 kHz, 51 ms) upon the collection of product ions. The most abundant product was that giving the signal at 121 Th. Peaks to at higher mass/charge than 137 Th in part B and 121 Th in part C are due to contaminant ions. Figure 2D shows the isolation (0.05 V amplitude, 300-330 kHz, 4 ms) of the secondgeneration fragment, 121 Th. Note that all of the unwanted ions are ejected from the trap. However, this comes at the expense of just 25% efficiency in retention of 121 Th. Figure 2E shows the activation of 121 Th (0.003 V amplitude, 300 kHz, 51 ms) and collection of third-generation ions at 107 and 91 Th. The imperfect isolation of acetophenone (77% with 20% residual ion abundance) in the tandem mass spectrometry experiment can

be attributed to the well-known fact that acetophenone undergoes unimolecular fragmentation on the time scale of ion trap experiments.39 Parent ion fragmentation caused either by metastable decay or by collision-induced dissociation during the isolation period is responsible for the low isolation efficiency. Supporting this conclusion is the fact that the sum of the heights of the peaks due to the two ions in the isolation experiment is, within experimental error, identical to the total parent ion peak height in the single stage mass spectrum. As noted above, the MS/MS/ MS experiment with acetophenone was performed by isolation (0.05 V amplitude, 380-340 kHz, 4 ms) of the fragment ion at 105 Th (86% efficiency) with 100% ejection of 77 Th. Subsequent activation (0.002 V amplitude, 390 kHz, 51 ms) of this ion, the stable benzoyl ion, yielded the lower mass fragment at 77 Th in low abundance (0.06 V). This is consistent with known thermochemistry: molecular ions with 1-4 eV of internal energy can lose CH3• to form the benzoyl fragment ion at 105 Th. Only ions with internal energy greater than 4 eV can fragment further to give 77 Th.40 The reduced quality of the data seen in the experiments just described, as compared to data taken using commercial ion traps, is the result of MSn experiments being less efficient in a miniCIT. As the dimensions of the trap are decreased, the RF amplitude must be decreased, the RF frequency increased, or both in order to keep the Mathieu parameter qz constant for ions of a given mass/charge ratio. The average axial trapping potential, Dz, varies linearly with respect to both qz and the RF amplitude.41,42 Thus, at constant mass/charge and qz, Dz will decrease as trap dimensions are decreased, and ejection of the parent ion from the trap becomes more competitive with its fragmentation. For example, a rough estimate of Dz (at a qz value of 0.4) for 152 Th is 38 V for a full-sized quadrupole ion trap (r0 ) 10.00 mm, z0 ) 7.83 mm), operating at 1.05 MHz and VRF of 760 V, but it is only 3.5 V for the mini cylindrical ion trap CIT (r0 ) 2.5 mm, z0 ) 2.89 mm, VRF ∼140 V, Ω ) 2.00 MHz). Because the trapped ions are ejected using lower amplitude excitations, more care must be taken in optimizing pressure and CID excitation waveform amplitude in the mini-CIT, to sufficiently activate the precursor ion before it is ejected. This is accomplished by gently exciting the ion using a lower amplitude excitation waveform, which is applied for a longer period of time. Effect of Experimental Parameters. Experimental conditions were optimized by varying the operating parameters, including the nature and pressure of the buffer gas, the SWIFT waveform amplitude, the isolation (“notch”) width, and the CID activation waveform amplitude and its duration. Unless otherwise noted, the results that follow are those observed for p-nitrotoluene, although to the extent investigated, they are typical. Both room air (at ambient humidity and temperature) and helium were used as buffer gases. Pressure effects were investigated while CID excitation was fixed at 51 ms duration and at 0.005 V amplitude. At lower pressures, the absolute peak height of the parent ion (137 Th) was four times greater for He (1.7 V, (39) Soni, M. H.; Wong, P. S. H.; Cooks, R. G. Anal. Chim. Acta 1995, 303, 149-162. (40) Lambert, J. Organic Structural Spectroscopy; Prentice Hall PTR: Upper Saddle River, NJ, 1997. (41) Fulford, J. E.; March, R. E. Int. J. Mass Spectrom. Ion Physics 1979, 30, 39. (42) Major, F. G.; Dehmelt, H. G. Phys. Rev. 1968, 91, 170.


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3.3 × 10-5 Torr, corrected for ion gauge response) than for room air (0.4 V, 4.4 × 10-5 Torr). However, the total fragment ion signals were ∼3 times greater for air (1.3 V) than for He (0.4 V), making the total ion signals similar in the two cases, 1.7 V for air vs 2.1 V for He. At higher pressure, 1.0 × 10-4 Torr corrected ion gauge reading for either gas, the parent ion peak height is still ∼4 times larger for He than air (2.4 vs 0.6), but the total fragment ion peak height is the same (0.9 V). Total ion signal (sum over all mass/ charge values) is 1.5 V for air versus 3.3 V for He. Both sets of observations are consistent with He’s being better at stabilizing metastable parent ions. In addition, these observations are also consistent with better trapping efficiency by He bath gas, especially at higher pressures, but with air being the better gas in terms of CID efficiency.43 To study the effects of changing the amount of He buffer gas, the manifold pressure was increased 15-fold, from 3.3 × 10-5 to 5 × 10-4 Torr by the addition of He but with the amount of p-nitrotoluene remaining constant. Parent ion abundance, fragment ion abundance, and total ion peak height all increased by a factor of 2.4 (see values in Table 1, column 1). Among the fragment ions, the increase was not uniform, with 121 Th increasing in intensity by a factor of 6 and the other peaks heights changing much less, a simple consequence of the different energy requirements for the several dissociation pathways. The increase in total ion peak height is consistent with higher trapping efficiency and possibly more efficient stabilization of parent ions and the fragment ion (121 Th) of lowest critical energy with increased collision probability. The amplitude and the width of the frequency “notch” in the SWIFT waveforms used to isolate the ions of interest were found to have profound effects on the mass spectra. For example, in the case of methyl salicylate, when the amplitude of the isolation waveform for the molecular ion was increased from 0.04 to 0.06 V, a 2.5-fold decrease in parent peak height was observed. Similar effects have been observed in other ion trap experiments and are associated with perturbation of the ion population being retained in the trap. Another observation with literature precedent44 is that increasing the duration of the CID excitation waveform increased the amount of dissociation. For example, in the case of methyl salicylate, after isolation (4-ms SWIFT pulse) of the molecular ion (152 Th), an increase in the CID activation time from 51 to 451 ms led to a factor of 7 increase in the abundance of the fragment ion at 120 Th (from 0.2 to 1.5 V). Meanwhile, the height of the peak at 152 Th decreased from 1.6 to 0.2 V. The CID energy was fixed at 0.005 V (300 kHz), and the pressure was held constant (3.6 × 10-4 Torr, corrected ion gauge response for He). It is noteworthy that the total peak height is constant to within the experimental reproducibility ((0.1 V), strongly suggesting that ion loss is minimal, even over extended periods of time. Finally, the effect of increasing the amplitude of the CID excitation waveform was investigated. Increasing fragmentation was observed with increasing CID excitation amplitude, up to a certain level. For p-nitrotoluene, when the CID amplitude increased from 0.001 to 0.008 V, total fragment ion abundance increased by a factor of 2. However, above 0.008 V, the parent (43) Goeringer, D. E.; McLuckey, S. A. Rapid Commun. Mass Spectrom. 1996, 10, 328-334.

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Figure 3. Mass spectrum (partial) of 100 ppm toluene in water, introduced through an external MIMS system showing resolution, R ) m/∆m ) 100, using the full-width half-maximum definition.

ion signal decreased with no corresponding increase in total fragment ion signal. This behavior is well-known 45-47 and is usually the result of two factors: (i) the translationally excited parent ions are more easily ejected from the ion trap and (ii) the additional internal energy allows for sequential dissociation of product ions, forming ions below the low-mass cutoff, which are not observable. Thus, for each compound, CID energy must be carefully tuned to obtain optimal dissociation. Moreover, all of these experiments point to the combination of low voltage amplitude CID waveforms applied over long times for optimal ion activation and efficient fragment ion retention in the trap. Limit of Detection and Resolution. The limit of detection for the CW simulant, methyl salicylate, was estimated as 1 pg in an experiment in which it was measured as the neat vapor. This sample was obtained by taking an aliquot of a 1 ppb solution of methyl salicylate in methanol and evaporating the solvent. When the organic vapor was introduced into the mass spectrometer, it provided a signal for 30 s, and the mass spectrum was recorded for only 1 s of this time. A blank mass spectrum, obtained from 1 µL of pure methanol prepared and dried as described above, was subtracted from the methyl salicylate mass spectrum. This yielded a mass spectrum, with a single peak at 152 Th, with an abundance that was seven times that of the noise. Memory effects from high concentration samples previously introduced into the mass spectrometer were continuously observed in both samples and blanks, necessitating background subtraction. This is an expected consequence of operating the mass spectrometer at ambient temperature to obtain the benefit of reduced power consumption. Note that while a full mass spectrum was recorded, there is only one ion of significant abundance, so the experiment has only the specificity of a single ion monitoring experiment. Presented in Figure 3 is a partial spectrum of toluene, introduced through the external MIMS33 system (100 ppm toluene in water, sample flow rate 1 mL/min).48,49 The resolution, R ) m/∆m, is estimated from this spectrum as 100, using the fullwidth half-maximum definition. Another estimate, based on the methyl salicylate mass spectrum, indicates approximately unit resolution at 152 Th. (44) Hao, C. Y.; March, R. E. Int.. J. Mass Spectrom. 2001, 212, 337-357. (45) Charles, M. J.; McLuckey, S. A.; Glish, G. L. J. Am. Soc. Mass Spectrom. 1994, 5, 1031-1041. (46) Liere, P.; March, R. E.; Blasco, T.; Tabet, J. C. Int. J. Mass Spectrom. Ion Processes 1996, 153, 101-117. (47) Yost, R. A.; Enke, C. G.; McGilvery, D. C.; Smith, D.; Morrison, J. D. Int. J. Mass Spectrom. Ion Processes 1979, 30, 127-136. (48) Patterson, G. E. Ph.D. Thesis, Purdue University, West Lafayette, 2002. (49) Riter, L. S. Ph.D. Thesis, Purdue University, West Lafayette, 2001.

Figure 4. Mass spectrum of air sampled on-line, while a cough drop (active ingredient menthol) is held 3 cm from the membrane inlet of the mass spectrometer. The labeled peaks are characteristic of menthol.

Air and Water Sampling. To monitor organic compounds in air, a permeation MIMS device was installed on the mass spectrometer. Untreated room air was pulled through this internal MIMS system at a rate of 4 L/min. During air sampling, a cough drop (active ingredient, menthol, 12 mg/cough drop) was held 3 cm from the inlet of the MIMS system. Figure 4 shows the mass spectrum of the sampled air; the labeled peaks are characteristic of menthol.35 It is anticipated that the concentration of menthol in the sampled air is very much lower than 150 ppm, the saturated concentration of menthol in air; however, the true value is unknown. A drawback of the current MIMS system is the long rise and fall time (total analysis time ∼4-6 min), which is again the result of the system, including the membrane, being operated at ambient temperature. Elevating the temperature of the membrane allows for faster rise and fall times and greater sensitivity, especially for less volatile compounds. However, this occurs at the cost of additional power consumption. (See next section) Preliminary work, both in the laboratory and in the field,49 has been conducted on water samples, using an external MIMS configuration. The field work involved battery operation of the miniature mass spectrometer at a wastewater site. Chloramines were analyzed using single-stage and tandem mass spectrometry. Current Developments. A second generation of the miniature instrument is currently being constructed and tested, as briefly described in the accompanying paper.48 This second generation instrument (version 7) has a custom-built vacuum manifold, which is much smaller and lighter than the commercial vacuum manifold in the previous system (version 5). This manifold also accommodates an off-axis detector and conversion dynode. It houses the same size ion trap (r0 ) 2.5 mm) and has an internal MIMS inlet fitted with a Nichrome wire (30 gauge, type A, 3-5 Ω) coiled around the membrane, which allows a current (300 mA) to be passed to desorb accumulated analyte (not the entire MIMS system, only the membrane itself is directly heated). This allows improved performance of the MIMS system as a result of heating of the membrane, but this is achieved by a method that uses a very small amount of power compared to that needed to continu-

Figure 5. Mass spectra of methyl salicylate in air introduced through the internal MIMS inlet: (A) 400 ppb, without heating; (B) 10 ppb, using trap-and-release and heating the membrane. The signal at 100 Th in (B) is due to background.

Figure 6. Methyl salicylate multiple ion monitoring traces (sum of relative abundances of 92, 120, and 152 Th). The sequence of events was 30 s of air sampling followed by 30 s of heating (marked A), then 60 s of air sampling followed by either 15 s (plot A) or 30 s (plot B) of air sampling while a wintergreen-flavored breathmint was held close to the air inlet of the instrument (marked B), followed by a 60-s heating period during which the vapors of methyl salicylate from the breath mint were desorbed into the mass spectrometer (marked C), then 60 s of air sampling room air (marked D), 30 s of heating, and finally, a 1-min air sampling period (marked E). Note that twice the exposure time yielded a sample signal (marked C) of twice the peak height (9 V verses 4.5 V) while in each case, the blank signals (marked A and E) are approximately equal before and after the sample signals, indicating the lack of carryover

ally heat the entire membrane assembly. In addition, improvements in software allow multiple ion monitoring. An informative comparison of the limits of detection of the original miniature CIT instrument, version 5, and the improved version has been made using standard samples of methyl salicyAnalytical Chemistry, Vol. 74, No. 24, December 15, 2002

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late, prepared in air and introduced into the mass spectrometer via the internal MIMS system. Figure 5A dispalys a mass spectrum of 400 ppb methyl salicylate in air; it shows a signal-to-noise ratio of 8:1 at 92 Th and 3:1 at 152 Th. This experiment was repeated with the membrane operated in a trap-and-release mode, with only the membrane being heated and its temperature being cycled during the experiments in order to save the power. Figure 5B is a spectrum of 10 ppb methyl salicylate in air recorded with this heated MIMS system. As can be seen, the signal-to-noise ratio of this spectrum is even greater than that of the nonheated MIMS system, even when using 40 times less analyte. These data emphasize the need for compromises between power consumption and sensitivity in portable instruments. Additional data taken using the newer version of the instrument include the on-line detection of wintergreen breathmints (distributed by Callard & Bowser-Suchard Inc., Rye Brook, NY) shown in Figure 6. Figure 6A and B are plotted on the same absolute scales to allow direct comparison of peak heights. In both traces, a blank experiment was performed at point A, which gave a response slightly smaller than 2 V. After sampling room air with a crushed wintergreen confectionary held near the instrument for a given sampling time (in plot A, this is 15 s; for plot B, this was 30 s), the membrane was heated (point C) and the sampled methyl salicylate desorbed into the mass spectrometer. The 15 s exposure yielded a 4.5 V peak height with a 23-s rise time and a 26-s fall time, while a 30-s exposure to the sample yielded a 9 V peak height with a 32-s rise time and a 30-s fall time. A blank was again collected after the sampling, and the intensity was recorded again and found to be slightly smaller than 2 V, indicating there was no significant carryover. Conditions could be altered such that the sensitivity was higher, but in initial tests, this did lead to carryover effects. CONCLUSIONS The analytical performance of a new miniature mass spectrometer based on a miniature cylindrical ion trap (r0 ) 2.5 mm)

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has been established. The instrument has been shown to be capable of MSn (n ) 1-3) experiments with a variety of environmentally significant compounds, including the chemical warfare agent simulants DMMP and methyl salicylate, as well as p-nitrotoluene and acetophenone. Resolution is estimated at 100, m/∆m (full width half-maximum). The limit of detection for methyl salicylate is estimated as 1 pg. As an example of the ability to sample and monitor organic compounds in air, a permeation MIMS device was installed on the mass spectrometer and successfully used to sample organic compounds in room air at low levels. This miniature instrument exhibits the advantages of relatively high sensitivity and good resolution, which makes possible real-time monitoring for volatile compounds in air at the low-parts-per-billion level. Future work will involve testing different ionization methods, further development of a fully miniaturized MIMS/SS-MIMS sample introduction system for handling air and water samples, and construction of an even smaller, lighter-weight version of the instrument. ACKNOWLEDGMENT We acknowledge funding from NAVSEA/NSWC Crane no. N00164-00-C-004, Purdue University Center for Sensing Science and Technology, State of Indiana 21st Century Research and Technology Fund, and the Office of Naval Research (no. N0001497-0251). We thank the staff of the Jonathan Amy Facility for Chemical Instrumentation.

Received for review July 29, 2002. Accepted October 16, 2002. AC0204956

Analytical Performance of a Miniature Cylindrical Ion Trap Mass

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