Time-of-flight mass spectrometers (TOF MS) determine the mass-to-charge ration (m/z) of an ion by accelerating ions through the TOF MS towards a detector and recording a measurement for the ion travel time within the TOF MS to the detector. Some implementations have utilized two TOF MS consecutively (TOF/TOF). Other implementations of TOF MS may include gas chromatography (GC-TOF MS) or liquid chromatography (LC-TOF MS) to handle a sample before TOF MS carry out the analysis. Additionally, such implementations of GC-TOF MS and LC-TOF MS may utilize a quadrupole ion trap (LC-Q-TOF and GC-Q-TOF), such as U.S. Patent Application 2013/0068942 incorporated herein by reference.
Parameters of TOF MS depend on efficient coupling to pulsed and continuous ion sources. To form ion packets, TOF MS commonly employ pulsed acceleration of stagnated ion clouds. In early implementations, ions were accumulated in electron impact (EI) ion sources and were pulse-accelerated into a TOF MS. A method of delayed ion extraction from an EI source was proposed in [W. C. Willey, I. H. McLaren, Rev. Sci. Instr. 26, 1150 (1955)] to improve the resolution of linear TOF MS. Dodonov et al., in SU 1681340, describe an effective solution for converting continuous ion beams into pulsed ion packets with the aid of an orthogonal accelerator (OA). In a sense, an ion beam is stagnated in the direction of TOF separation. Compared to the prior pulse deflection methods, the OA method strongly improves the duty cycle of pulsed conversion. The OA pulsed conversion method appears generic (i.e. applicable to any type of ion source) and has been widely adopted in commercial instrumentation for LC-TOF, LC-Q-TOF and GC-Q-TOF instruments.
Another method of preparing short ion packets—pulsed bunching of moving and initially wide ion packets—has been long-known in nuclear physics for transformations of ion packets in time-energy space. Such transformations of the ion packets include time compression, energy-spread reduction, or time-focal plane adjustment. To form initial ion packets (prior to the bunching step) nuclear physics commonly employs the chopping of continuous ion beams, say with mechanical choppers, like rotating disk with slits. Thus, while pulsed acceleration is applied to stagnated ion clouds, bunching is applied to already moving ion packets.
Axial pulsed bunching of ion packets has been adopted in the field of mass spectrometry and has been explored in matrix-assisted laser desorption ionization (MALDI) instrumentation. Delayed extraction (DE) in MALDI TOF employs bunching of short ion packets formed by a pulsed laser shot. As described in U.S. Pat. No. 5,760,393, U.S. Pat. No. 5,625,184, and U.S. Pat. No. 6,541,765 (each of which is incorporated herein by reference), this DE method has improved time-focusing and source robustness by avoiding energetic collisions between extracted ions and ejected material known as the MALDI plume. Applying axial bunching of ion packets in TOF-TOF tandems is described in U.S. Pat. No. 5,739,529, U.S. Pat. No. 6,703,608, U.S. Pat. No. 6,717,131, U.S. Pat. No. 6,300,627, U.S. Pat. No. 6,512,225, U.S. Pat. No. 6,621,074, U.S. Pat. No. 6,348,688, U.S. Pat. No. 6,770,870, U.S. Pat. No. 7,667,195, U.S. Pat. No. 8,461,521, WO2011028435, US2012168618, and WO2013134165, each of which is incorporated herein by reference. Bunching of moving ion packets was also proposed after pulse ejecting multipoles, as described in U.S. Pat. No. 5,689,111 (FIG. 8), which is incorporated herein by reference.
Known methods of pulsed conversion were initially adopted in recently emerged multi-reflecting Time-of-flight mass spectrometry (MR-TOF MS). MR-TOF MS with ion spatial confinement achieved by a periodic lens, described in GB2403063A and WO2005001878 (each of which are incorporated herein by reference), provides an exceptional combination of mass resolving power and data acquisition speed. Resolution is strongly enhanced, rising nearly proportional to flight path extension. While the flight path in singly reflecting TOF MS is about three times the instrument size, commercial MR-TOF MS Citius HRT by LECO Corp provides a 16 m flight path in a 0.6 m long analyzer (i.e. allows for trajectory folding at more than a factor of twenty-five). Potentially, the flight path can increased to few hundred meters in 1 m long instrument if using cylindrical analyzer geometry as described in GB2478300 and WO2011107836, which are incorporated herein by reference.
However, sensitivity of MR-TOF MS has been limited by the duty-cycle limitations of a pulsed converter. If employing an orthogonal accelerator (OA), as described in WO2007044696, the duty cycle is reduced to less than 0.3-0.5%—at a pulsing period of 1 ms and at an OA length of 6-8 mm—due to analyzer acceptance limitations. If employing and alternative axial trap converter, the charge throughput becomes limited to 1E+7-1E+8 ion/sec as described in “Linear Ion Trap with Axial Ejection as a Source for a TOF MS” by B. Kozlov et. al. ASMS 2005. With recent improvements of ion sources, like ESI sources providing 1E+9 ion/sec or EI sources providing up to 1E+11 ion/sec, the effective duty cycle of trap converters becomes even lower than the duty cycle of the OA.
The problem has been notably softened with introduction of the multiplexing method based on encoded frequent pulsing (EFP®), as described in WO2011135477, incorporated herein by reference. The average pulse frequency is increased from 1 kHz to 100 kHz, which improves the OA duty cycle to approximately 30% and which also improves both the dynamic range of the analyzer (limited to approximately 1000 ion/packet of one mass by space charge effects) and the dynamic range of the detector and data system. The method has been extended onto various tandems as described in WO2013067366, WO2013192161, and WO2014176316, each incorporated herein by reference.
The scheme of orthogonal acceleration (OA) has drawbacks. First, the OA scheme is very sensitive to minor distortions of field-free conditions when a slow continuous ion beam fills the OA gap. Surface and mesh contamination affect an ideal OA operation. Second, to form sharp ion packets, the beam spatial-angular emittance has to be low, usually under 100 eV*mm2*deg2, (which may be realized by 1-2 mm and 1-2 deg at 30-50 eV energy) which requires trimming of a continuous ion beam prior to OA and, thus, introduces ion losses. Collisional radiofrequency (RF) ion guides, like gas filled RF-only quadrupoles, help in significant reduction of ion beam emittance to keep those losses moderate. However, RF ion guides have limited charge throughput, and spatial losses at the OA entrance appear dependent on ion currents above 10 nA, when using intense sources such as EI or ICP. Third, reaching small turn-around times for higher resolving power requires large field strength in the OA and large amplitudes (above 2 kV) of pulse generators. This may require the use of at least two pulse generators, which adds cost and becomes challenging in combination with a 100 kHz pulsing rate when using encoded frequent pulsing. Fourth, further reduction of turn around time (desired for higher resolution) by using high acceleration fields in OA is limited by the associated rise of ion packet energy spread, exceeding MR-TOF energy acceptance.
Thus, there still remain some practical problems associated with orthogonal acceleration for MR-TOF MS. And a need remains for a lower cost and more effective solution for coupling continuous or quasi-continuous ion sources to MR-TOF analyzers.