Advantages of Time-of-Flight Mass Spectrometry Over Quadrupole MS

Time-of-flight mass analyzers have significant advantages over quadrupoles for many applications. Simultaneous measurement of all mass-to-charge ratios with time-of-flight mass spectrometry improves speed and sensitivity, ensures that no important information is lost, and makes it easier to identify analytes and interpret measurements.  The increased mass resolving power and mass accuracy of time-of-flight mass analyzers help identify compounds and characterize complex mixtures.

Overview

Time-of-Flight Mass AnalyzerQuadrupole Mass Analyzer
AcquisitionMeasures all m/Q simultaneouslyMeasures individual m/Q in a sequence
Speed1000 full spectra per second1000 measurements per second of single m/Q
Mass Resolving
Power,

R = M/dM
>10,000
R~constant over mass range
Separate isobars
Determine chemical formula
Unit mass
dM ~constant over mass range
Isobars not separable
Relative Mass
Accuracy, dM/M
4 ppm = 4mTh/Th at 1000 ThChanges over mass range
Mass Accuracy, dM0.001 Th at 300 Th0.5 Th
Mass Range1 Th to 10,000 ThTypically 10 Th to 500 Th

How Quadrupole and TOF Mass Analyzers Work

Quadrupole and time-of-flight (TOF) mass analyzers separate ions of different mass-to-charge ratio (m/Q) via fundamentally different strategies, which results in different detection capabilities.

Quadrupole Mass Analyzer

A quadrupole mass analyzer is a mass filter: only ions with a specific mass-to-charge ratio (m/Q) reach the detector.  A spectrum is recorded by scanning through measurement of each m/Q of interest.

Figure 1 demonstrates the measurement process.  An electric RF field is used to guide ions along the central axis of the quadrupole. A superimposed DC field is used to selectively destabilize certain ions and eject them from the quadrupole. The strength of both fields can be adjusted so that only a small m/Q range has a stable trajectory through the quadrupole. All ions with m/Q outside this range will be ejected, while ions inside this range are detected.  To record an entire mass spectrum, the range of stability is scanned across the entire m/Q range, making a measurement at each step.


Figure 1. Concept of quadrupole measurement. Ions of only one mass-to-charge ratio are measured at a time; all other ions are discarded. In this figure, selected ion monitoring is performed to measure the three smallest mass-to-charge ratios (blue, yellow, gray) and the largest, red ion is not measured.

Time-of-Flight Mass Analyzer

A TOF mass analyzer separates ions based on their velocity as they travel through a flight region, often called the flight tube. The measurement is similar to a race: a group of ions is accelerated by an extractor (start of the race), which causes them to drift through the flight tube (the race course) toward a detector (the finish line). The time elapsed between the extraction and collision with the detector is recorded. Intuitively, a molecule with a large mass should travel more slowly than a molecule with a small mass, so, the elapsed time indicates the molecular mass. For ions of identical charge, this is the case.

Figure 2 shows this process in detail.  In the TOF extractor at the beginning of the flight region, ions encounter an electric field that accelerates all of them to a similar kinetic energy E.  More precisely, ions gain kinetic energy that is proportional to their charge Q. For ions with the same charge, E/Q is approximately constant.

Kinetic energy E is related to mass and velocity:

E = ½ mv2

This means:

E/Q = ½ m/Q v2 ~ constant

Therefore, ions with smaller m/Q fly more quickly through the TOF chamber and reach the detector earlier. The instrument measures the time of flight of each ion from extractor to detector, which is then converted into a mass spectrum.



Figure 2. Concept of time-of-flight measurement. The extractor gives all ions the same kinetic energy. They travel into a field free region (the TOF chamber). A reflectron increases resolution. The detector counts how many ions arrive as a function of time. All ions are measured in each microsecond-length flight. Thousands of flights are added together to report a single measurement.

In the animation above, the flight lasts a few seconds. In TOFWERK instrumentation, the flight is much faster: tens of thousands of flights per second, or flight times of about 10 µs to 100 µs. In cases where a spectral rate of 20’000 spectra/second is not required, multiple TOF extractions are accumulated into a single spectrum. For example: when a TOF is operated at 20’000 extractions/s, the data of 2000 extractions can be accumulated into a single mass spectrum, resulting in a rate of 10 spectra/s.

Modern TOF instrumentation uses clever electronic and mechanical design to improve the resolving power, including design elements like the reflectron, and in practice there are many steps between ions impacting the detector and the mass spectrum displayed on the instrument screen.

Full-Spectrum vs. Scanning

In contrast to the quadrupole analyzer, which counts ions of only a single mass-to-charge ratio in each measurement, a TOF analyzer counts the number of ions of all m/Q  in each measurement. Simultaneous detection of all ions is preferable to both the selected ion monitoring (SIM) and to full-spectrum scans of quadrupole mass spectrometers.  

Full-spectrum quadrupole scans require a certain dwell time per ion. It can take quite a long time to scan through a full spectrum. This results in a very slow measurement and the loss of a great deal of information. For example, Figure 3A shows a measurement of a single breath made with a Vocus 2R PTR-TOF, at a 4 Hz acquisition rate. 241 different VOCs were quantified in this sample, not including VOC in the background matrix. It would take over a minute to measure the same number of ions with a quadrupole mass analyzer, using the same measurement dwell time of 0.25 seconds. By the time the quadrupole full-spectrum scan is finished (Figure 3B), the breath is long since complete.


Figure 3. Time-series measurement of a single breath, beginning at about 1.5 seconds. Left: TOFMS measurement of the breath. The markers show when measurements are taken for each ion. Right: The same measurement of breath, as would be measured by QMS. The markers show when measurements are taken for each ion.

Sensitivity Decreases as More m/Q Are Added to Quadrupole Scan

During the quadrupole dwell on a single m/Q, ions of all other m/Q are discarded. This directly impacts the overall sensitivity. Imagine a ten-second measurement of a calibration standard. A quadrupole and a TOF each measure ten mass-to-charge ratios. The quadrupole can spend no more than 1 second accumulating signal for each mass-to-charge ratio, while the TOF accumulates the full ten seconds of signal for each m/Q. It’s clear that the TOF will measure a higher number of counts for each m/Q and therefore have a higher sensitivity over the 10 second period.

Simultaneous TOF Detection Means Important Species Are Not Missed

A quadrupole measurement can be made faster by measuring only a small number of pre-selected ions (selected ion monitoring, or SIM). However, the ions that are not monitored may contain important information. For example, Figure 4 shows part of a chromatographic elution (GC) measured with a TOFWERK electron ionization (EI) TOF at a 5 spectra/s acquisition rate. To resolve the chromatographic peaks, a quadrupole operator could select no more than three ions for SIM. The actual EI spectrum of the molecule contained in the largest chromatographic peak contains more than 200 ions. Peak identification via spectrum matching with a NIST library is far more robust using a 200-ion full-spectrum scan.

Additionally, a scientist using SIM must be very sure that they will never be interested in any other VOCs in the sample. This is especially important, and extremely difficult to do, for non-targeted analysis, in which the exact composition of the sample is not known ahead of time. By measuring all ions all the time, the measurement becomes “future-proof”: if research or a new application indicates that a new molecule is important, the analyst can revisit previously collected TOF data, where the newly interesting molecule has already been measured.

Figure 4. GC elution measured with EI-TOF. The main figure shows the chromatographic elution. At least eight chromatographic peaks are visible, with widths of a few seconds. The colored lines and markers show where a QMS using SIM would make a measurement. The inset shows the actual full EI mass spectrum of the largest peak, including more than 200 ions.

Simultaneous Detection Correlates Species Within the Sample

A quadrupole produces staggered measurements: each ion in a sequence, rather than simultaneously. This effect is known as “spectral skewing”.

This is important for applications such as chemometric fingerprinting, or source apportionment for ambient air monitoring. If the VOC composition of the sample changes rapidly, it is not possible to find the relative ratios of VOCs.  As an example, Figure 5 shows a Vocus Elf PTR-TOF measurement of aromatics in ambient air. This measurement is from a mobile laboratory in a European city, and the composition of the measured air changed extremely rapidly.


Figure 5. Rapidly changing aromatic concentrations during mobile monitoring.  QMS shows spectral skewing whereas TOFMS does not.

The relative ratios of benzene, toluene, xylene, and larger aromatics indicate the source: in this case, gasoline vehicle exhaust. With the corresponding 3-ion SIM quadrupole measurement (QMS), it is impossible to determine the relative ratios of the different aromatics and the source identification and apportionment becomes much more difficult.

Another application where fast, simultaneous acquisition of the full mass spectrum is beneficial is inductively coupled plasma mass spectrometry (ICP-MS) for elemental or isotopic analysis. In ICP-MS, the TOF mass analyzer excels over sequential mass analyzers when large numbers of isotopes must be measured over an extremely short time span. Such short signals are produced, for example, by single-particles (micro-droplets or nanoparticles) or by fast (low-dispersion) laser ablation cells which enable fast multi-elemental imaging.

Figure 6 shows an example of steel nanoparticles that were analyzed for Cr, Fe, Ni, and Mo. The signal of a single steel nanoparticle is less than 0.5 ms in duration. Whereas TOFWERK’s icpTOF (an ICP-MS instrument equipped with a TOF analyzer) reliably characterizes the complete signal from individual particles, a sequential mass spectrometer (e.g., QMS) would miss a significant portion of the signal by measuring the elements one-by-one. Not only would this lead to lower overall signal intensities but also to incorrect mass ratios.

Figure 6. Time-resolved signal from steel nanoparticles composed of Fe, Cr, Ni, Mo in a MilliQ water dispersion. The particles were measured with the icpTOF R. Top: Transient signal of a single steel particle detected with 90 µs time resolution. 3 TOF extractions were averaged and the total counts per particle are given. Bottom: Simulated transient signal of the same particle recorded with a sequentially measuring quadrupole mass analyzer. The data were simulated from the TOF signal using 90 μs dwell time on each isotope, with no analyzer settling time. Sensitivity is decreased by up to 33-fold due to sequential detection of the four isotopes. Element mass ratios measured by the quadrupole deviate from the actual ratios by 76-270%.

High Resolving Power of TOF Enables Peak Identification

The resolving power of a quadrupole mass analyzer is limited by the machining precision of the quadrupole rods and the capability of the electronics. Quadrupole mass analyzers are typically operated with unit mass resolution, and even the very highest-end quadrupole mass analyzers on the market today have a resolving power of only about R = M/dM (FWHM) = 3000-4000 Th/Th . A mass spectrum from a quadrupole mass analyzer with unit mass resolution is compared to a Vocus S PTR-TOF mass spectrum with a resolving power of R = 5000 Th/Th in Figure 7.


Figure 7. Comparison of PTR-QMS and PTR-TOFMS data.

With unit-mass resolution, isobaric compounds cannot be distinguished. Isobaric compounds have the same nominal mass, but different elemental composition. Isobars may have different behavior in the sample, so it is important to be able to measure them separately (Figure 8).

Figure 8. Data from a Vocus S PTR-TOF with a resolving power of 5000. Top: Time series of three isobaric compounds detected at nominal mass-to-charge ratio 69 Th. Each isobar has clearly different behavior. Bottom: Mass spectra at selected time points, showing three clearly resolved isobaric peaks.

Higher resolving power also allows the determination of elemental composition. This is crucial for compound identification and cannot be done with unit-mass resolving power. In the example shown in Figure 9, high mass resolving power (R ≈ 5000 Th/Th) and high relative mass accuracy (within 5 ppm) were necessary to identify the compound detected at 97.045 Th as fluorobenzene, rather than 3-furaldehyde (97.028 Th) or 2-ethylfuran (97.065 Th).

Figure 9. High mass resolving power and high mass accuracy are needed to robustly determine the elemental composition of detected compounds.

Conclusion

The advantages of time-of-flight mass analyzers compared to quadrupoles are clear. Samples can be measured faster and with no spectral skewing. For the same mass range, a TOF analyzer will measure each ion more sensitively. Since all ions are included in each simultaneous full-spectrum scan, no important information is missed or discarded. Finally, the much higher resolving power of TOF allows the separation of isobars and the determination of elemental formula.

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