Tandem-in-time instruments

Multiple mass analyzers exist that can perform tandem mass spectrometry. Some use a tandem-in-space configuration, such as the triple quadrupole mass analyzers illustrated (Fig.3.9). Others use a tandem-in-time configuration and include instruments such as ion-traps (ITMS) and Fourier transform ion cyclotron resonance mass spectrometry (FTICRMS or FTMS). A triple quadrupole mass spectrometer can only perform the tandem process once for an isolated precursor ion (e.g., MS/MS), but trapping or tandem-in-time instruments can perform repetitive tandem mass spectrometry (MS ), thus adding n 1 degrees of structural characterization and elucidation. When an ion-trap is combined with HPLC and photodiode array detection, the net result is a profiling tool that is a powerful tool for both metabolite profiling and metabolite identification. 

Ion traps are tandem-in-time instruments, i.e., they perform the steps of precursor ion selection, ion activation and acquisition of fragment ion spectra in the very same place. This advantageous property allows the multiple use of a single QTT to perform not only MS but also MS and higher order MS experiments - indeed a very economic concept. Depending on the abundance of the initial precursor ion, its fragmentation behavior - and of course, on the performance of the QIT - MS experiments are possible. [138] However, in contrast to tandem-in-space instruments, tandem-in-time instruments do not support constant neutral loss and precursor ion scans. 

Tandem Mass Spectrometer An instrument capable of performing multiple mass (mjz) analyses. There are two major categories (1) tandem-in-space instruments (triple quadmpole and Q-TOF), (2) tandem-in-time instruments (QIT and FTICR). 

If a reactant gas is introduced into the collision cell, ion-molecule collisions can lead to the observation of gas-phase reactions. Tandem-in-time instruments facilitate the observation of ion-molecule reactions. Reaction times can be extended over appropriate time periods, typically as long as several seconds. It is also possible to vary easily the reactant ion energy. The evolution of the reaction can be followed as a function of time, and equilibrium can be observed. This allows the determination of kinetic and thermodynamic parameters, and has allowed for example the determination of basicity and acidity scales in the gas phase. In tandem-in-space instruments, the time allowed for reaction will be short and can be varied over only a limited range. Moreover, it is difficult to achieve the very low collision energies that promote exothermic ion-molecule reactions. Nevertheless, product ion spectra arising from ion-molecule reactions can be recorded. These spectra can be an alternative to CID to characterize ions. 

The tandem-in-time instruments are mostly ion-trapping devices, including ion trap and FT-ICR. They operate in a time sequence in the scan function to yield MS/MS data, mostly product ion spectra. No additional mass analyzer is required. In the case of an ion trap, the scan function begins with the isolation of ions of interest with ejection of all other ions from the ion trap, followed by (a) translational excitation of ions by applying a supplementary RF voltage to the trap and (b) mass analysis of the product ions using resonant ejection. 

The product ion scan entails the mass selection of a precursor ion in the first stage (Qj), fragmentation (CID or ETD) in the collision cell, and then mass analysis of all resultant fragment masses in the second stage of mass analysis (Q3) (Figure 7(b)). This experiment can be performed by beam (tandem-in-space) or trap (tandem-in-time) instruments. It is commonly performed to identify transitions used for quantification by tandem MS or as part of an exercise in structural elucidation. 

The types of tandem mass spectrometers capable of performing MS/MS experiments fall into two basic categories tandem in space and tandem in time. Tandem-in-space instruments have discrete mass analyzers for each stage of mass spectrometry examples include multisector, triple-quadru-pole, and hybrid instruments (instruments having mixed types of analyzers such as a magnetic sector and a quadrupole). Tandem-in-time instruments have only one mass analyzer where each stage of mass spectrometry takes place in the same analyzer but is separated in time via a sequence of events. Examples of this type of instrument include Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometers and quadrupole ion traps, described in Chapter 3. 

MSk Experiments Comparison of MS3 Spectra of Product Ions with MS/MS Spectra of Proposed Product Ion Structures Formed via Independent Sythesis. With the development of tandem-in-time instruments such as FT-ICRs and ion traps, multistage MS experiments are becoming routine. Thus, the structures of CID product ions can be interrogated via CID using a further stage of MS. In some instances, if a suitable independent synthesis can be achieved, the resultant MS3 spectrum can be compared with the MS/MS spectra of ions of known structure, thereby facilitating ion structure assignment. 

In both tandem-in-space and tandem-in-time instruments, the most common experiment is for the first analyzer to select specific ions from the total ion beam arriving from the ion source. Next, the selected ions undergo collision-induced dissociation (CID) in a pressurized cell followed by the analysis of the product ions in the second analyzer. In tandem-in-time the same analyzer is used for both scans, but at different times. The resulting product ion spectra (or precursor and neutral loss spectra in other forms of MS/MS analysis) provide vital structural information for the identification of small molecules (such as drug metabolites) as well as complex biomolecules. Selected reaction monitoring (SRM), another mode of MS/MS operation, provides highly specific and sensitive quantification of target analytes. 

In tandem-in-time mass spectrometers all operations take place within a single-ion storage device, but at different times. The most common tandem-in-time instrument is the quadrupole ion trap (QIT). The ongoing development of a higher-sensitivity counterpart, the linear ion trap (LIT), will presumably lead to an eclipsing of the QIT. 

In the tandem in-time instruments, all three steps of MS/MS operation are performed in the same region, but are separated in time, whereas in the tandem in-space instruments, these steps are carried out in different regions. 

As trapping mass analysers, ions are either formed within the volume of the trap (as in GC/MS) or injected into the trap (as in LC/MS) where they are trapped and stored for m/z analysis. The various stages of the MS" analyses are performed by applying appropriate voltages to the three trap electrodes as a function of time. Thus, ion traps are often called tandem-in-time instruments, vs QqQs which are called tandem-in-space instruments, i.e. the first mass analyses, dissociation and second mass analysis steps are performed in different spatial regions of the instrument. 

Tandem-in-Time Spectrometers. Tandem-in-time instruments form the ions in a certain spatial region and then at a later time expel the unwanted ions and leave the selected ions to be dissociated and mass analyzed in the same spatial region. This process can be repeated many times over to perform not only MS/MS experiments, but also MS/MS/MS and MS" experiments. Fourier transform ICR and quadrupole ion-trap instruments are well suited for performing MS" experiments. In principle, tandem-in-time spectrometers can perform MS/MS experiments much more simply than tandem-in-space instruments because of the difficulty in providing different ion focal positions in the latter. Although tandem-in-time spectrometers can readily provide product-ion scans, other scans, such as precursor ion scans and neutral loss scans, are much more difficult to perform than they are with tandem in space instruments. 

Note In contrast to tandem-in-space instruments, tandem-in-time instruments neither support precursor ion nor constant neutral loss scanning. While product ion scans just need a precursor to be isolated prior to its fragmentation, both precursor ion and constant neutral loss scan rely on the simultaneous application of selection plus scanning or double scanning, respectively. Fulfilling two criteria at the same time requires two distinct analyzers at work. 

Tandem MS has been more or less successfully performed with a wide variety of analyzer combinations. What analyzers to combine for a certain application is determined by many different factors, such as sensitivity, selectivity, and speed, but also size, cost, and availability. The two major categories of tandem MS methods are tandem-in-space and tandem-in-time, but there are also hybrids where tandem-in-time analyzers are coupled in space or with tandem-in-space analyzers. Moreover, the ongoing development of faster electronics and high-voltage circuits as well as better software tools and hardware control devices constandy open up new possibilities of making innovative combinations of analyzers for specific applications. In this chapter a few examples of commercially available tandem MS instruments are presented. A brief summary of their weaknesses, strengths, and main areas of applications is given. 

In order to perform two consecutive mass-analyzing steps, two mass analyzers may be mounted in tandem. This technique is applied with beam transmitting devices, i.e., TOF, sector and quadrupole analyzers can be combined that way tandem-in-space, Fig. 4.15). Alternatively, a suitable mass analyzer may be operated by combining selection, activation, and analysis in the very same place. Quad-mpole ion trap (QIT) and ion cyclotron resonance (ICR) instruments can perform such tandem-in-time experiments. 

FT-ICR mass spectrometers belong to the tandem-in-time category of instruments. The stage of precursor ion selection (MSI) is accomplished by selectively storing the ions of interest, whereas all others are ejected by means of a suitably tailored excitation pulse, e.g., using the SWIFT technique. [206] FT-ICR mass spectrometers are also capable of MS . 

These are not the only types of tandem mass spectrometers. There are numerous configurations of instruments that are based on the type of ion separation and many new terms associated with these instrument types. For example, there are instruments known as ion traps. The ion trap is a device that can measure mass, fragment a selected mass (as could be done in a collision cell) and then measure the mass of the fragment. The product ion produced by this all in one device is the same product ion that would be produced in a tandem quadrupole instrument. However, there is only one mass analyzer that functions as both the collision cell and mass measuring device. These types of instruments are sometimes referred to as tandem mass spectrometers, but are not abbreviated as MS/MS. The MS/MS analysis is done by separating the analysis in time (tandem in time) rather than two devices separated in space. A more generic term is best suited. This term is MS , where the n represents... 

Common tandem-in-space instruments employ a quadrupole as the first mass analyzer, a multipole collision cell (usually hexapole) operated in RF-only mode, and then either a second quadrupole or a TOF tube as the second mass analyzer. These instruments are termed triple or tandem quadrupole and quadrupole-time-of-flight mass spectrometers. 

As instrumentation developed, tandem-in-time approaches were developed using ion trap and Fourier transform ion cyclotron resonance (FT-ICR) instruments. During tandem-in-time experiments, the sequential stages of mass selection, CID, and mass analysis are performed within the same, trapping, mass analyzer. 

In contrast to triple quadrupole instruments, where MS-MS experiments can be conducted in space in separate regions of the instrument, ion traps enable MS-MS sequentially in the same physical space, and thus, occur tandem in time. After the ions have been formed an trapped, a parent ion is selected by resonance ejection of all ions except those of the selected m/z ratio. This is done by applying a resonance ejection radiofrequency voltage to the end-cap electrodes which stimulates motion of the ions in the axial direction. The next step in the MS-MS sequence is to effect collisionally... 

A third type of MS/MS instruments is a hybrid of tandem-in-space and tandem-in-time devices, including the Q-trap (QQ-2D-linear trap) [45] and the ion trap-FT-ICR (2D-linear ion trap-FT-ICR) [46]. The Q-trap takes the configuration of triple quadrupole, with the third quadrupole replaced by a 2D-linear ion trap. The uniqueness of this design is that the 2D-linear ion trap component can be used to perform either (a) a normal quadrupole scan function in the RF/DC mode or (b) a trap scan function by applying the RF potential to the quadrupole. It is well-suited for both qualitative and quantitative studies. In the case of ion Trap-FT-ICR, it combines ion accumulation and MS" features of a 2D-linear ion trap with excellent mass analysis capability (mass resolution, mass accuracy, and sensitivity) of FT-ICR. 

Trapping-type instrument capable of tandem-in-time experiments and can be linked to ToF analyzer (QIT-ToF). h Trapping-type instrument capable of tandem-in-time experiments and can be linked to Q, FTICFt, or Orbitrap analyzers (e.g., QqLrT-FTICFt, and LIT-Orbitrap). 

Trapping-type instrument capable of tandem-in-time experiments and can be configured to analyze fragments generated externally (e.g., QqFTICR or LIT-FTICR). 

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