Instrumentation
Fourier Transform Mass Spectrometry Charles L. Wilkins Department of Chemistry University of Nebraska Lincoln, Neb. 68588
Less than 10 years ago, it was possi ble for Henis to accurately observe in a review article in this JOURNAL (1), "Indeed icr mass spectrometers are more limited with respect to mass range and resolution t h a n are other types of mass spectrometers." A little more t h a n two years afterward, we suggested in an instrumentation arti cle (2), "Ion cyclotron resonance spec trometry is becoming established as an important analytical technique in its own right and a useful complement to conventional mass spectrometry." In both reviews, which sought to focus on the analytical potential of ICR, the emphasis of the discussions was pri marily how the unique capabilities of the method for studying ion-molecule reactions could be used to advantage in a n analytical chemistry context. We reported some results from our labora tory which established t h a t certain op erational enhancements were realiza ble by adding a digital computer to the ICR mass spectrometer system, and rather conservatively suggested t h a t the application of computer-as sisted experimental techniques would assist in ICR's transition from a physi cal chemist's research instrument to an analytical tool. During the inter vening years, some truly exciting de velopments in ICR mass spectrometry have taken place. T h e purpose of this article is to assess the analytical impli cations of these advances and to at t e m p t to project the future role of ion cyclotron resonance in analysis.
Principles Several of the earlier reviews (1-4) and an excellent new book by Lehman and Bursey (5) outline in detail the fundamental principles governing ion cyclotron resonance spectrometry. Ac cordingly, only a brief qualitative de scription of the basic phenomena will be included here. ICR spectrometry's unique properties derive from the be 0003-2700/78/0350-493A$01.00/0 © 1978 American Chemical Society
havior displayed by ions placed in a strong magnetic field. Such ions travel in circular paths perpendicular to the applied magnetic field. If no energy is added or lost by such an ion, the force exerted on it by the field is coun terbalanced by the centrifugal force of its motion. Thus, Equation 1 can be written mv2/r = eBv
(1)
where m is the mass of the ion e, the charge; Β the magnetic field strength; υ its velocity; and r the radius of its path. When this equation is rear ranged, the ratio of velocity to radius is, at a fixed magnetic field strength, a constant dependent upon only the mass and charge of the ion. T h e angu lar frequency coc in rad/s defined in Equation 2 is therefore ωα = υ/r = eB/m
(2)
a characteristic and different ion cy clotron frequency for each ion with the same charge, b u t different mass. In its various forms, ion cyclotron res onance mass spectrometry consists of taking advantage of the properties of this fundamental phenomenon to de tect and "count" ions present in the spectrometer cell after they have been generated in a suitable source region.
Instrumentation It will be helpful in understanding the newest advances to consider the development of ICR instrumentation along with the factors t h a t prove lim-
iting with each of the successive de signs. T h e first application of ICR in mass spectrometry was t h a t of Hippie, Sommer, and Thomas in 1949 (6, 7). However, these investigators used the method primarily for gas analysis a t masses below 50 and did not develop it as a general mass spectrometric technique. In their instrument, called the omegatron, after ions were gener ated in the cell they were excited with a radiofrequency radiation. Under these conditions, for any ion with OJ C /2 π equal to the imposed radiofre quency, absorption of energy will occur, the ion will be accelerated, and its path changed from a circular one (with respect to the axis of the cell) to an Archimedes spiral. As a result, an ion collector placed in the appropriate position can collect ions in resonance, whereas those not in resonance are not collected. With such a design, each ion can alternately be brought into reso nance by either varying the magnetic field or the oscillating electric field frequency, resulting in a mass spec trum. A difficulty of this design is t h a t stray ions can also be collected at the collector electrode, causing errors im possible to correct. One additional fea ture incorporated in the omegatron was provision of means for applying a trapping voltage, to prolong ion resi dence times. T h e first commercial ICR instru ment (introduced by Varian Asso ciates in 1966 and removed from pro duction a few years later) used a drift cell in which a marginal oscillator de tected instantaneous power absorp tion of sample ions as they drifted through the analyzer region. In this 2.5 cm-square by 8.6 cm-long threesection cell, ions were first formed in a source region, then drifted into an analyzer region where they were irra diated and detected, and finally col lected at a total ion collector. Its major shortcoming was its limited ion trap ping capability (in the range 1 to sev-
ANALYTICAL CHEMISTRY, VOL. 50, NO. 4, APRIL 1978 · 493 A
eral milliseconds) and its low resolu tion and restrictive upper mass range limit (ca. unit resolution at m/e = 200). A theoretical resolution limit for this kind of cell is determined by the ion drift time through the analyzer section. Comisarow and Marshall have derived an equation describing resolu tion in the zero pressure limit, using the linewidth at half peak height to define resolution (8). In Equation 3, e is the charge in multiples of elemen tary charge, Β the magnetic field in kilogauss, m the mass in amu, and Τ is given in milliseconds. Notice partic ularly t h a t resolution is a linear func tion of detection time (i.e., the longer ions can be seen, the higher the resolu tion). m/m50%
= eBT/5.769 Χ 10~ 4 m (3)
Because of the short residence (and hence, detection) times, the next major development effort was aimed at prolonging those times. Clever trapped ion cell designs by McMahon and Beauchamp (9) and Mclver (10), which allow ion "storage" for periods on t h e order of a second or more, re sulted. Nevertheless, resolution achievable in the trapped-cell mode with conventional instruments is not significantly greater t h a n t h a t ob tained with the original drift cell de sign, although the mass range has been extended as high as 500 with unit resolution. Operation of the single sec tion trapped cell is generally in the pulsed mode, where the temporal be havior of single ions is usually ob served for the purpose of kinetic stud ies. If an entire spectrum were to be collected with this cell, measurement would normally be done, as with the drift cell, at a fixed radiofrequency while scanning the magnetic field. This mode of producing spectra limits the speed with which measurements can be made, because of the difficulty in making rapid changes in the mag netic field strength. For the conventional ICR spectrom eters described, other designs can lead to improved mass range and mass measurement accuracy, but slow scan rates and low resolution will probably continue to limit the generality of their analytical capabilities. It is pri marily because of these limitations t h a t researchers interested in expand ing the general-purpose analytical utility of ICR mass spectrometry have turned to investigations of Fourier transform approaches.
Fourier T r a n s f o r m M S
Within the past several years, ana lytical chemistry has been a primary beneficiary of t h e minicomputer tech nology revolution. Dramatic advances in the state-of-the-art of digital elec tronics have allowed such analysis methods as Fourier transform infrared and nuclear magnetic resonance spec trometry to become not only practical, but commonplace. Previous instru-
BAND PASS FILTER
MIXER
EXCITATION
ADC
MINICOMPUTER
netic field) scanning modes. As a re sult, when a time domain signal is sampled at Ν equal intervals, signalto-noise ratio is enhanced by a factor Λ/Ν • In the infrared spectral case, the advantage becomes one-half this fac tor because the half-silvered mirrors used in interferometers reject half the incident radiation. This time advan tage, called the Fellgett advantage (18), permits spectroscopists to com plete a spectrum in 1/N of the time
CELL
PULSE
FREQUENCY
ICR
PROGRAMMER
SYNTHESIZER
SPECTROMETER
GATING AND CONTROL PULSES
KEYBOARD AND DISPLAY
MAGNETIC DISK
Figure 1. Block diagram of Fourier transform ion cyclotron resonance mass spectrometer system
mentation articles have lucidly de tailed the principles and advantages of both Fourier and H a d a m a r d trans form spectroscopy methods (11-16), most recently in the comprehensive discussion of Marshall and Comisarow (17). It is not, then, surprising t h a t such techniques would suggest them selves for possible application to ICR spectrometry. Although complete dis cussions of the principles involved are included in the references cited above, the qualitative aspects of the use of time domain measurements, and their transformation to the frequency do main will be outlined here. Briefly, the primary contribution of Fourier transform methods in both infrared spectrometry and nuclear magnetic resonance spectrometry is the fact that, in such experiments, measurements can be made in a frac tion of the time required by conven tional frequency (or, for N M R , mag-
494 A · ANALYTICAL CHEMISTRY, VOL. 50, NO. 4, APRIL 1978
required for a frequency domain mea surement and obtain the same signalto-noise ratio, or alternatively, to achieve increased sensitivity in the same total measurement time. N M R spectrometry and ion cyclo tron resonance, at least superficially, have much in common, with the pri mary difference being the nature of the phenomena observed and the ab solute frequencies involved. In the N M R experiment, a brief radiofre quency pulse (typically from 1 to 50 MS for 13 C and XH N M R ) is used to ex cite simultaneously the nuclei absorb ing over a frequency range of 10 kHz or less (12). Subsequently, the free in duction decay of the ensemble of ex cited nuclei is observed, and the re sulting time domain sequence (each point of which contains information regarding all portions of the frequency range covered) is subjected to a Fouri er transformation t h a t converts it to
Figure 2. Ion excitation decay (IED) plot for bromoform
27.99 28.00 28.01 28.02 28.03 28.04 amu
Figure 5. Fourier transform mass spectrum of mixture of nitrogen, carbon monoxide, and ethylene illustrating high-resolution measurement
Time domain data obtained during approximately 30-ms observation period
251 253 255 257 259 261
150.0
160.0
170.0
180.0
190.0
200.0
210.0
220.0 230.0 amu
240.0
250.0
260.0 270.0
280.0
290.0 300.0
Figure 3. a) Fourier transform mass spectrum of bromoform. b) Expanded scale plot of molecular ion region of bromoform spectrum
150
200
250
300
350
400
450 500 550 600 650 700 750 amu Figure 4. Fourier transform mass spectrum of perfluorokerosene (PFK) illustrating broad mass range measurement
the frequency representation preferred by spectroscopists. Relaxation of the nuclei as a function of time is the phenomenon monitored in this case. As mentioned earlier, in an ion cyclotron resonance spectrometer, ions (rather than nuclei) absorb radiofrequency energy at frequencies (typically between 0 and 1 MHz) characteristic of their m/e ratios if magnetic field is held constant. As in the N M R experiment, it was found convenient in the earlier instruments, particularly those employing the three-section drift cell mentioned earlier, to operate at fixed frequency and to scan magnetic field, alternately bringing ions of each mass into resonance at t h a t frequency to obtain a spectrum. Continuing the analogy, it is also possible to visualize an experiment for ICR superficially identical to t h a t carried out in Fourier NMR. First, ions are generated, then the ions (rather than nuclei) are subjected to irradiation over a broad frequency range, and the time dependent behavior of the ensemble of excited ions is observed. Fourier transformation of the time domain data thus obtained yields a mass spectrum, rather than an N M R spectrum, but it too is simply the frequency domain representation of the timeintensity data collected during the data acquisition period. Here, however, the principal phenomenon observed is, rather than de-excitation from nuclear excited states (the relaxation process in NMR), the decay of ions back to thermal energies as a result of m o m e n t u m loss through collisional processes. One very important consequence of this difference in the relaxation processes involved (intravs. intermolecular) is the possibility that resolution for Fourier ICR, in contrast to NMR, can be improved by using more dilute samples. Another important difference is the bandwidth for the ICR experiment can be as much as 1 MHz in contrast to the 10 kHz or less involved in Fourier carbon NMR. Comisarow and Marshall, working at the University of British Columbia, have verified the feasibility of Fourier transform ion cyclotron resonance and described their results in a series of communications beginning in 1974 (8, 17, 19-25). Examples of actual spectral measurements they reported in 1975 (23) include a spectrum of tris(perfluoroheptyl)azine t h a t clearly shows the molecular ion at m/e = 1885; an ultrahigh-resolution spectrum of a mixture of CO, N2, and ethylene in the m/e = 28 region where m/m50% = 250 000, and a spectrum of perfluorokerosene (obtained in 10 segments) extending from m/e = 69 to m/e = 605. These encouraging results obtained with a prototype instrument
suggested the enormous potential of F T - I C R for analytical applications. As a result, several groups have begun actively pursuing such development. Most recently, Mclver has advocated (and demonstrated) a technique whereby instead of temporally separating ion excitation and detection as in the Comisarow and Marshall formulation of the Fourier transform experiment, detection is begun simultaneously with irradiation (26). His experiment is carried out on a somewhat slower time scale and uses a new capacitance bridge detector of his own design which appears to be promising. Both approaches utilize a frequency synthesizer as the excitation source and incorporate minicomputers as integral parts of the spectrometer system. Figure 1 shows a block diagram of a Fourier ion cyclotron resonance mass spectrometer, and Figures 2—5 are representative examples of recent spectra recorded with a contemporary prototype instrument. Analytical Prospects for FT-ICR It is clear at this point t h a t the transition of ICR to a general analytical tool may well be possible using Fourier transform methods. Because of the potential high sensitivity of ICR and the latitude it permits in choice of reagent ions (for ion-molecule reaction and chemical ionization studies), it may well compete with conventional high-resolution and chemical ionization mass spectrometers. T h e high sensitivity arises because the residence times possible in an ICR spectrometer make ion-molecule reactions observable at pressures from five to six orders of magnitude lower than in a conventional source. As a result, only small quantities of samples need to be used, and partial pressures of 10~ 7 to 1 0 - 8 torr are adequate for ionization of nonvolatile materials. Another source of high sensitivity is the 100% ion collection efficiency realized in ICR spectrometers, in contrast to the thousandfold worse efficiency of sector instruments. Of course, the use of electron multipliers (not possible in F T - I C R ) allows the sector instruments to recapture part of the sensitivity lost due to inefficiency. One example of the suggested high sensitivity is Mclver's experimental observation t h a t sample consumption rates of about 1 ng/s are adequate for producing identifiable ICR signals (27). Let us return briefly to Comisarow and Marshall's work: At the 1975 "Annual Conference on Mass Spectrometry and Allied Topics" (23), they projected a Fourier ICR mass spectrometer would have the capability of producing mass spectra up to 10 000 times faster than a conventional ICR
instrument or to be up to 100 times as sensitive. Concurrently, such an instrument would have the capability of yielding high-resolution mass spectra (routine resolution 10 000 up to m/e = 1000) calibrated throughout the mass range and would retain all the capabilities of conventional ICR spectrometers. These predictions, together with the experimental data thus far obtained using prototype instruments, suggest a number of exciting analytical possibilities. The Future It could be t h a t Fourier ICR will have some of the impact on mass spectrometry t h a t Fourier NMR has had on nuclear magnetic resonance spectrometry. In particular, it may ultimately provide the means for achieving another order of magnitude in trace analysis sensitivity for organic materials over t h a t obtainable today with state-of-the-art conventional mass spectrometers. Furthermore, the expected capability of obtaining an entire spectrum over a moderate mass range [for example, from a minimum mass of 125 amu, with a resolution of 10 000 (m/m2s%)] using a 14 000 gauss magnetic field and a few hundred milliseconds data acquisition time, will certainly have major impact on the practice of gas chromatography/mass spectrometry, should it prove possible to successfully interface the ICR spectrometer to a gas chromatograph in a way that permits F T - I C R . These kinds of analytical advances have yet to be demonstrated, although the evidence is clear t h a t there is a very reasonable chance t h a t they will come within the next two or three years. Judgment should be reserved until the experimental results are in, but it does appear t h a t analytical ion cyclotron resonance spectrometry is on the threshold of assuming its role as an analytical method of major importance. Acknowledgment It is a pleasure to acknowledge the valuable and critical contributions to this article by my colleague Michael L. Gross. T h e spectra in Figures 2-5 were provided by Nicolet Technology Corp., Mountain View, Calif. 94041. References (1) J.M.S. Henis, Anal. Chem., 41 (10), 22A (1969). (2) M. L. Gross and C. L. Wilkins, ibid., 43 (14), 66A (1971). (3) J. D. Baldeschwieler, Science, 159, 263 (1968). (4) J. D. Baldeschwieler and S. S. Woodgate, Ace. Chem. Res., 4, 114 (1971). (5) T. A. Lehman and M. M. Bursey, "Ion Cyclotron Resonance Spectrometry", Wiley-Interscience, New York, N.Y., 1976.
ANALYTICAL CHEMISTRY, VOL. 50, NO. 4, APRIL 1978 · 497 A
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a higher degree of statistical control, implement computational techniques to validate the measurement process, a n d control experimental parameters to facilitate data collection and computational fine-tuning.
(6) J. Hippie, H. Sommer, and H. Thomas, Phys. Rev., 76,1877 (1949). (7) H. Sommer, H. Thomas, and J. Hippie, ibid., 82, 697 (1951). (8) M. B. Comisarow and A. G. Marshall, J. Chem. Phys., 64, 110 (1976). (9) T. B. McMahon and J. L. Beauchamp, Reu. Sci. Instrum., 43, 509 (1972). (10) R. T. Mclver, Jr., ibid., 41,555 (1970). (11) M.J.D. Low, Anal. Chem., 41 (6), 97A (1969). (12) T. C. Farrar, ibid., 42 (4), 109A (1970). (13) G. Horlick, ibid., 43 (8), 61A (1971). (14) J. A. Decker, Jr., ibid., 44 (2), 127A (1972). (15) M. Margoshes, ibid., 43 (4), 101A (1971). (16) A. J. Senzel, Ed., "Instrumentation in Analytical Chemistry", American Chemical Society, Washington, D . C , 1973. Refs. 2 and 11-15 included in this text. (17) A. G. Marshall and M. B. Comisarow, Anal. Chem., 47, 491A (1975). (18) P. Fellgett, J. Phys. Radium, 19,187 (1958). (19) M. B. Comisarow and A. G. Marshall, Chem. Phys. Lett., 25, 282 (1974). (20) M. Comisarow and A. G. Marshall, "Annual Conference on Mass Spectrometry and Allied Topics'', Philadelphia, Pa., May 1974. (21) M. B. Comisarow and A. G. Marshall, Chem. Phys. Lett., 26, 489 (1974). (22) M. B. Comisarow and A. G. Marshall, Can. J. Chem., 52, 1997 (1974). (23) M. B. Comisarow and A. G. Marshall, "Annual Conference on Mass Spectrometry and Allied Topics", Houston, Tex., May 1975. (24) M. B. Comisarow and A. G. Marshall, J. Chem. Phys., 62, 293 (1975). (25) M. B. Comisarow, Adv. Mass Spectrom., 7, in press. (26) R. T. Mclver, Jr., and R. L. Hunter, "Annual Conference on Mass Spectrometry and Allied Topics", Washington, D . C , May 1977. (27) M. L. Gross, University of Nebraska, private communication.
This book focuses on the strategy for optimizing experimental parameters in chemical analysis and minimizing components of variation with respect to the variable size simplex, Poisson probability distribution, and acceptability limits.
Validation of the Measurement Process A C S Symposium Series No. 63 J a m e s R. DeVoe, Editor Institute for Materials Research, National Bureau of Standards A symposium of Analytical
sponsored by the Division Chemistry of the American Chemical Society.
T h e minicomputer is broadening the scope of the analytical chemist by emphasizing microprocessors a n d digital computers in day-to-day data analysis. It permits the analytical chemist to establish
CONTENTS Statistical Control of Measurement Processes « Testing Basic Assumptions in the Measurement Process » Systematic Error in Chemical Analysis · Role of Reference Materials and Reference Methods in the Measurement Process · Optimization of Experimental Parameters in Chemical Analysis · Components of Variation in Chemical Analysis 207 pages (1977) clothbound $20.00 LC 77-15555 ISBN 0-8412-0396-2 SIS/American Chemical Society 1155 16th St., N.W./Wash., D.C. 20036 Please send copies of SS 63 Validation of the Measurement Process at $20.00 per copy. Π Check enclosed for $ ( 1 Bill me. Postpaid in U.S. and Canada, plus 75 cents elsewhere. Name Address City
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500 A · ANALYTICAL CHEMISTRY, VOL. 50, NO. 4, APRIL 1978
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Charles L. Wilkins is professor of chemistry at the University of Nebraska. His research interests include pattern recognition techniques, laboratory computer interfacing, and nuclear magnetic resonance and mass spectrometry.
