Tandem-in-space

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. 

A tandem-in-space mass spectrometer consists of an ion source, a precursor ion activation device, and at least two nontrapping mass analyzers. The first mass analyzer is used to select precursor ions within a narrow m/z range. Isolated precursor ions are allowed to enter the ion activation device, for example, a gas-filled collision cell, where they dissociate. Created fragments continue on to the second mass analyzer for analysis. The second mass analyzer can either acquire a full mass fragment spectrum or be set to monitor a selected, narrow, m/z range. In principle the second mass analyzer could be followed by more ion activation devices and mass analyzers for MSn experiments. However, due to rapidly decreasing transmission and increasing experimental 

Reference 5. With the advent of commercially available MALDI-TOF-TOF instruments the combination of off-line one- or two-dimensional LC-MALDI-MS/MS has become a popular alternative or rather a complement to LC-ESI-MS/MS in the proteomics community. 

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Scheme 7.5 Comparison of tandem-in-time (QQQ) and tandem-in-space (QIT) MS/MS...

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. 

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. 

Fig. 4.15. Tandem-in-space setups for different beam instruments magnetic four-sector instrument (a), magnetic sector-quadmpole hybrid (b), triple quadmpole (c), and ReTOF (d).

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. 

Boyd, R.K. Linked-Scan Techniques for MS/MS Using Tandem-in-Space Instra-ments. Mass Spectrom. Rev. 1994, 13, 359-410. 

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). 

There are two classes of tandem instrument. The original development was CID tandem-in-space MS involving arrangement of two mass analyzers separated by a collision cell. A cartoon of a tandem-in-space instrument is shown in Fig. 10. 

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. 

There are three MS/MS experiments that are of use in carbohydrate analysis. These can be depicted schematically (Fig. 11) and are described using a tandem quadrupole instrument as an example. Quadrupole-based tandem-in-space instruments operate at low CID energies (up to 100-200 eV). 

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. 

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. 

The deliberate generation of fragments is a valuable tool in structure elucidation and quantification. It is mainly carried out as a second mass analysis after determination of the mass per charge (m/z) ratio of the molecular ions. This approach is called tandem mass spectrometry and it can be carried out either as tandem-in-space using a triple quadrupole (or combinations of... 

Trapping mass spectrometers can also be used as tandem mass spectrometers. Unlike beam-type mstruments, which are referred to as tandem in space, trapping mass spectrometers are tandem in time, meaning that ions are held in one region of space while the parent ion is selected and dissociated and the daughter ion analyzed sequentially in time. The ability to perform tandem mass spectrometry is inherent in the design of trapping mass spectrometers. Gen-... 

For the beam-type mass analyzers (sector, ToF, and Q), each stage of mass analysis is performed in discrete mass analyzers usually separated by a collision cell. This arrangement is called tandem-in-space. The use of multiple analyzers means that analyzers can be independently selected for the different stages of analysis based on the desired performance characteristics. 

Figure 7 Scan modes for a tandem-in-space instrument, the triple quadruple (QqQ). (a) Full scan all source ions are passed through to Q3 while Q1 and q (collision cell) are set to the RF-only mode, (b) Production scan Qi is set to pass a selected ion (precursor ion). This is fragmented in the collision cell and products are analyzed by scanning Q3. (c) Precursor scan Q1 scans all the source ions into the collision cell for collision-induced dissociation (CID). Q3 is set to pass a selected product ion. A signal recorded at Q3 is correlated with the corresponding precursor ion passing through Q-i. (d) Neutral loss scan Q-i is set to scan ions into the collision cell for CID. The Q3 scan is offset by a specified mass, equal to the mass of the neutral, relative to Qi. (e) Selected reaction monitoring (SRM) an ion selected in Q1 is fragmented and a specific fragment is then recorded after selection by Q3. SRM is commonly used in quantitative work to improve assay selectivity and sensitivity.

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