Time-of-flight mass spectrometry (TOFMS): From niche to mainstream
Introduction
The classical methods of mass spectrometry stem directly from those pioneered by J.J. Thomson over 100 years ago [1]. They rely on the deflection of accelerated ions by magnetic fields. By contrast, time-of-flight mass spectrometry (TOFMS), as its name suggests, depends only on a time measurement. It could thus be argued that the measurement of the flight time of an ion is the simplest method of determining its mass.
The most straightforward variation of the technique measures the flight time of an accelerated ion as it passes down an evacuated pipe: m/q = 2 V/v2, where m and q are the molecular mass and charge, V is the accelerating potential, and v is the ionic velocity, determined by the ion's kinetic energy (1/2 mv2 = qV), and measured by the flight time [2]. If only singly charged ions are present, the lightest group reaches the detector first, followed by groups of successively heavier mass.
Nevertheless, the technique does require rather precise time measurements, which were not available until after World War II [3]. Apparently W.E. Stephens (Fig. 1) of the University of Pennsylvania was the first to propose a TOFMS instrument; his abstract presented at the April 1946 meeting of the American Physical Society [4] reads: “A Pulsed Mass Spectrometer with Time Dispersion: Advances in electronics seem to make practical a type of mass spectrometer in which microsecond pulses of ions are selected every millisecond from an ordinary low-voltage ion source. In traveling down the vacuum tube, ions of different M/e have different velocities and consequently separate into groups spread out in space. If the ions are collected in a fixed Faraday cage and the current amplified, then pulses of current corresponding to different ion M/e will be dispersed in time. If the amplified current pulses are put on the vertical plates of an oscillograph whose sweep is synchronized with the pulses, then an M/e spectrum of the ions will be exhibited. This type of mass spectrometer should offer many advantages over present types. The response time should be limited only by the repetition rate (milliseconds). The indication would be continuous and visual and easily photographed. Magnets and stabilization equipment would be eliminated. Resolution would not be limited by smallness of slits or alignment. Such a mass spectrometer should be well suited for composition control, rapid analysis, and portable use. A mass spectrometer of this type is being constructed.”
In fact, Stephen's mass spectrometer was not actually constructed until several years later [5], by which time other TOFMS instruments had been built [6,7]. However, the abstract does indeed describe the type of TOFMS device that was constructed within the next few years.
We may note that the advantages of the TOFMS mass spectrometer claimed by Stephens were rather modest. In particular, its resolution was determined entirely by μsec measurements, neglecting the improvements that could be made by nsec electronics. Also the “unlimited” mass range of the instrument was not mentioned, thus ignoring the possibility of measuring the masses of large biomolecules. Both these capabilities were to appear in succeeding decades.
Section snippets
The first practical TOF
The history of time-of-flight mass spectrometry begins for practical purposes with the work of Wiley and McLaren [8–10]. They described a two-field pulsed ion source that could produce either space focusing or velocity focusing, but not both simultaneously. They concluded:
Both the best compromise and the quality of the resulting resolution depends on the actual initial space and energy distributions. Lag systems give preferred treatment to energy resolutions; and no lag systems to space
The coincidence TOF mass spectrometer
In 1960 Rosenstock [12] proposed a coincidence mass spectrometer in which the time measurement was initiated by detection of a secondary electron produced by a gas phase ionization event, and time measurement terminated by detection of the corresponding positive ion at a second detector. A schematic diagram of the apparatus is shown in Fig. 2. The coincidence principle was previously used in studies of nuclear phenomena and in measuring the time-of-flight of high energy particles, but this was
The first commercial TOF
The first commercial TOFMS instrument was manufactured by the Bendix Aviation Corporation, in Cincinnati, Ohio and was introduced as the commercial Model 12-101 in 1965, but prototypes were used by several investigators beginning as early as 1956. It was especially important to have a commercial TOFMS mass spectrometer available because of the reluctance of many users to engage in instrument construction. This instrument employed the focusing conditions developed by Wiley and McLaren [8–10] and
Death of TOF-MS?
The Bendix mass spectrometer allowed coupling with gas chromatography (GC–MS) [20], and enjoyed considerable success; it was estimated that in 1962 one-third of the mass spectrometers in use in the United States were time-of-flight instruments [21, p. 11]. However, the attitude of the mass spectrometric community was not encouraging. Even later (∼1980), after the initial successes of desorption methods in analyzing large biomolecules, many workers in the magnetic sector field simply awaited the
What actually happened?
We may obtain a rough idea of the actual popularity of the TOFMS technique by recording the number of abstracts at the annual American Society for Mass Spectrometry (ASMS) meeting that include “TOF” or “time of flight” is shown in Fig. 5. Clearly this behavior shows that TOFMS had moved into the mainstream by the beginning of the new century, in sharp contrast to the beliefs of the mass spectrometric community in the 70s, as mentioned above. What caused this divergence from the common opinion?
Introduction of the reflecting geometry by Mamyrin
Techniques were actually available by 1980 to remedy the main perceived drawback of TOF measurements, their poor resolution. In addition to “time-lag focusing”, pioneered earlier by Wiley and McLaren [8–10], Mamyrin invented the “reflectron” in 1966, [29,30] (Fig. 5). This was published in Russian and generally unknown outside the then USSR. It was nearly a decade later before the significance of this work was recognized in the west. In this device, ions passed through a field-free region of
Desorption by fission fragments
Developments from a completely unexpected quarter transformed the time-of-flight landscape. This was the discovery of Macfarlane and Torgerson that the ions from spontaneous fission of 252Cf were effective in desorbing “difficult” biomolecular ions of previously inaccessibly large mass [36–42]. The discovery arose from an unrelated field, nuclear chemistry, in experiments that were intended to study the process of beta decay, so these workers deserve great credit for recognizing the potential
“FABULOUS FAB”
Very soon afterwards, workers at the University of Manchester Institute of Science and Technology (UMIST) developed a new technique that dramatically increased the usefulness of conventional (sector field) mass spectrometric methods, and threatened to replace time-of-flight methods altogether [50,51]. It was soon shown [52,53] that the technique was capable of analyzing the large molecules that had previously been the exclusive preserve of PDMS and its SIMS partners.
“FAB” was the name given to
Further integration
A meeting at Johns Hopkins University [55] was organized by Catherine Fenselau in September 1981 to compare the new methods of examining large biomolecules. The meeting included representatives from the laboratory that invented PDMS (Ron Macfarlane from Texas A&M), the one that invented FAB (Donald Sedgwick from UMIST), as well as from other laboratories working in the field, and theorists attempting to explain the results. This meeting, along with the conferences in Munster (IFOS II to IFOS
The invention of MALDI
At IFOS IV IN 1987 word came of an exciting development that had been presented at a joint Japan-China meeting earlier that year [56]. This was the production of ion clusters of mass >100 kDa using a slurry of glycerol and an ultrafine cobalt powder as matrix. The work was published in the next year [57], but the use of this type of matrix has seen limited use.
The Munster group had already been investigating the influence of the matrix in laser desorption [58]. They found that the use of a
MALDI-TOF-TOF
In early work Spengler and Kaufman [87] showed that fragmentation of ions in flight following production by MALDI-TOF could be used to determine amino acid sequence in peptides. This post-source decay (PSD) technique required programming the ion mirror voltage to sequentially focus segments of the fragmentation spectra. More recently tandem TOF-TOF instruments have been developed to determine the complete fragmentation spectrum in a single spectrum.
A tandem TOF-TOF was first described by Cotter
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