Ion-mobility spectrometry–mass spectrometry

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Ion-mobility spectrometry–mass spectrometry (IMS-MS), also known as ion-mobility separation–mass spectrometry, is an analytical chemistry method that separates gas phase ions on a millisecond timescale using ion-mobility spectrometry and uses mass spectrometry on a microsecond timescale to identify components in a sample.


Earl W. McDaniel has been called the father of ion mobility mass spectrometry.[1] In the early 1960s, he coupled a low-field ion mobility drift cell to a sector mass spectrometer.[2]

The combination of time-of-flight mass spectrometry and ion-mobility spectrometry was pioneered in 1963 at Bell Labs. In 1963 McAfee and Edelson published an IMS-TOF combination.[3] In 1967 McKnight, McAfee and Sipler published an IMS-TOF combination. Their instrument included an orthogonal TOF.[4] In 1969 Cohen et al. filed a patent [5] on an IMS-QMS system. The QMS at that time was an improvement compared to the TOFMS, because the TOFMS had a slow electronic data acquisition systems at that time. In 1970, Young, Edelson and Falconer published an IMS-TOF with orthogonal extraction.[6] They seem to have used the same system as McKnight et al. in 1967, incorporating slight modifications. Their work was later reproduced in the landmark book of Mason/McDaniel,[7] which is regarded as the “bible of IMS” by those skilled in the art.

In 1996 Guevremont et al. presented a poster at the ASMS conference [8] about IMS-TOF. In 1997 Tanner patented a quadrupole with axial fields which can be used as a drift cell for IMS separation. He also mentions the combination of these quadrupoles with an orthogonal TOFMS.[9] In 1998 Clemmer developed an IMS-TOF combination, using a co-axial IMS-TOF setup.[10] In 1999 Clemmer developed an IMS-TOF with an orthogonal TOF system.[11] This work led to the development of an ion mobility-quadrupole-CID-TOFMS instrument by Micromass in the UK and ultimately led Micromass / Waters corporation to develop of the worlds first commercial ion mobility-mass spectrometer instrument in 2006. The Synapt, as it is called, incorporates a pre ion mobility quadrupole allowing precursor ion selection prior to IMS separation further enhancing the flexibility of the ion mobility-mass spectrometry combinations. In 2013, Agilent Technologies released the first commercial drift tube ion mobility-mass spectrometer named 6560 with an 80 cm drift tube. Ion funnels are used to improve the ion transmission efficiency. The design thus greatly improved the sensitivity of ion mobility and allowed commercialization.[12][13]

A variation of IMS-MS is differential ion mobility spectrometry-mass spectrometry (DIMS-MS), in which gas phase ions are separated based on their ion mobility in varying strengths of electric fields.[14] This analytical method is currently being advanced by Gary Glish and the Glish Group.[14]


The IMS-MS is a combination of an ion-mobility spectrometer and a mass spectrometer.[12]

First the ion mobility spectrometer separates ions according to their mobilities. In a second step the mass spectrometer separates ions according to their mass-to-charge ratio. Such a combination is often referred to as a hyphenated separation or multi-dimensional separation.

There are different types of ion mobility spectrometers and there are different types of mass spectrometers. In principle it is possible to combine every type of the former with any type of the latter. However, in the real world, different types of ion mobility are coupled with different types of mass spectrometers to achieve reasonable sensitivity (will be discussed later).

Types of IMS-MS include drift tube IMS (DT IMS) or the traditional ion mobility spectrometer, DMS differential mobility spectrometer, a scanable filter, also called FAIMS,[1] and DMA differential mobility analyzer, a scanable filter.

Drift tube ion mobility does not employ RF voltage which may heat ions, and it can preserve the structure of the ions. The rotationally averaged collision cross section (CCS) which is a physical property of ions reflecting the shape of the ions can be measured accurately on drift tube ion mobility. The resolving power is high (CCS resolution can be higher than 100). Drift tube ion mobility is widely used for structure analysis. It is usually coupled with time-of-flight (TOF) mass spectrometer.[12]

High-field asymmetric-waveform ion-mobility spectrometry (FAIMS or RF-DC ion-mobility spectrometry) is a mass spectrometry technique in which ions at atmospheric pressure are separated by the application of a high-voltage asymmetric waveform at radio frequency (RF) combined with a static (DC) waveform applied between two electrodes.[15][16] Depending on the ratio of the high-field and low-field mobility of the ion, it will migrate toward one or the other electrode. Only ions with specific mobility will pass through the device. It is well known that the high RF field distort the conformation of the ions, FAIMS thus is a separation technique without reserving the structure of the ions and the CCSs of the ions cannot be measured.[17] Because FAIMS is a mass selector (other ions are excluded), the sensitivity in the scan mode is much lower than that of the drift tube ion mobility (all the ions are analyzed). Therefore, FAIMS is usually coupled with triple quadrupole mass spectrometer which is also ion selection type instrument.


The IM-MS technique can be used for analyzing complex mixtures based on differing mobilities in an electric field. The gas-phase ion structure can be studied using IM-MS through measurement of the CCS and comparison with CCS of standard samples or CCS calculated from molecular modelling. The signal-to-noise ratio is obviously improved because the noise can be physically separated with signal in IM-MS. In addition, isomers can be separated if their shapes are different. The peak capacity of IM-MS is much larger than MS so more compounds can be found and analyzed. This character is very critical for -omics study which requires analyzing as many compounds as possible in a single run. It has been used in the detection of chemical warfare agents, detection of explosives,[1] in proteomics for the analysis of proteins, peptides, drug-like molecules [18] and nano particles.{[19]} Recently, microscale FAIMS has been integrated with electrospray ionization MS and liquid chromatography MS to rapidly separate ions in milliseconds prior to mass analysis. The use of microscale FAIMS in electrospray ionization MS and liquid chromatography MS can significantly improve peak capacity and signal-to-noise for a range of applications including proteomics, and pharmaceutical analysis.[20]

Recently, gas-phase ion activation methods have been used to gain new insights into complex structures. Collision induced unfolding (CIU) is a technique in which an ion's internal energy is increased through collisions with a buffer gas prior to IM-MS analysis. Unfolding of the ion is observed through larger CCSs, and the energy at which unfolding occurs corresponds partially to noncovalent interactions within the ion.[21] This technique has been used to differentiate polyubiquitin linkages[21] and intact antibodies.[22]

See also[edit]


  1. ^ a b c Kanu AB, Dwivedi P, Tam M, Matz L, Hill HH (January 2008). "Ion mobility-mass spectrometry". Journal of Mass Spectrometry. 43 (1): 1–22. Bibcode:2008JMSp...43....1K. doi:10.1002/jms.1383. PMID 18200615.
  2. ^ McDaniel E, Martin DW, Barnes WS (1962). "Drift Tube-Mass Spectrometer for Studies of Low-Energy Ion-Molecule Reactions". Review of Scientific Instruments. 33 (1): 2–7. Bibcode:1962RScI...33....2M. doi:10.1063/1.1717656. ISSN 0034-6748.
  3. ^ McAfee KB, Edelson D (1963). "Identification and Mobility of Ions in a Townsend Discharge by Time-resolved Mass Spectrometry". Proceedings of the Physical Society. 81 (2): 382–384. Bibcode:1963PPS....81..382M. doi:10.1088/0370-1328/81/2/125.
  4. ^ McKnight LG, McAfee KB, Sipler DP (5 December 1967). "Low-Field Drift Velocities and Reactions of Nitrogen Ions in Nitrogen". Physical Review. 164 (1): 62–70. Bibcode:1967PhRv..164...62M. doi:10.1103/PhysRev.164.62.
  5. ^ Patent US 3621240
  6. ^ Young C, Edelson D, Falconer WE (December 1970). "Water Cluster Ions: Rates of Formation and Decomposition of Hydrates of the Hydronium Ion". The Journal of Chemical Physics. 53 (11): 4295–4302. Bibcode:1970JChPh..53.4295Y. doi:10.1063/1.1673936.
  7. ^ Mason EA, McDaniel EW (1988). Transport properties of ions in gases. New York: Wiley. p. 560. ISBN 978-0-471-88385-2.
  8. ^ Proceedings of 44th ASMS conference, p.1090
  9. ^ Patent WO9707530 (A1)
  10. ^ Henderson SC, Valentine SJ, Counterman AE, Clemmer DE (January 1999). "ESI/Ion Trap/Ion Mobility/Time-of-Flight Mass Spectrometry for Rapid and Sensitive Analysis of Biomolecular Mixtures". Analytical Chemistry. 71 (2): 291–301. doi:10.1021/ac9809175. PMID 9949724.
  11. ^ Hoaglund CS, Valentine SJ, Sporleder CR, Reilly JP, Clemmer DE (June 1998). "Three-Dimensional Ion Mobility/TOFMS Analysis of Electrosprayed Biomolecules". Analytical Chemistry. 70 (11): 2236–2242. doi:10.1021/ac980059c.
  12. ^ a b c Lanucara F, Holman SW, Gray CJ, Eyers CE (April 2014). "The power of ion mobility-mass spectrometry for structural characterization and the study of conformational dynamics". Nature Chemistry. 6 (4): 281–94. Bibcode:2014NatCh...6..281L. doi:10.1038/nchem.1889. PMID 24651194.
  13. ^ May JC, Goodwin CR, Lareau NM, Leaptrot KL, Morris CB, Kurulugama RT, et al. (4 February 2014). "Conformational Ordering of Biomolecules in the Gas Phase: Nitrogen Collision Cross Sections Measured on a Prototype High Resolution Drift Tube Ion Mobility-Mass Spectrometer". Analytical Chemistry. 86 (4): 2107–2116. doi:10.1021/ac4038448. PMC 3931330. PMID 24446877.
  14. ^ a b Isenberg SL, Armistead PM, Glish GL (September 2014). "Optimization of peptide separations by differential ion mobility spectrometry". Journal of the American Society for Mass Spectrometry. 25 (9): 1592–9. Bibcode:2014JASMS..25.1592I. doi:10.1007/s13361-014-0941-9. PMC 4458851. PMID 24990303.
  15. ^ Guevremont R (November 2004). "High-field asymmetric waveform ion mobility spectrometry: a new tool for mass spectrometry". Journal of Chromatography A. 1058 (1–2): 3–19. PMID 15595648.
  16. ^ Kolakowski BM, Mester Z (September 2007). "Review of applications of high-field asymmetric waveform ion mobility spectrometry (FAIMS) and differential mobility spectrometry (DMS)". The Analyst. 132 (9): 842–64. Bibcode:2007Ana...132..842K. doi:10.1039/b706039d. PMID 17710259.
  17. ^ Shvartsburg A, Li F, Tang K, Smith RD (February 2007). "Distortion of Ion Structures by Field Asymmetric Waveform Ion Mobility Spectrometry". Analytical Chemistry. 79 (4): 1523–1528. doi:10.1021/ac061306c. PMID 17297950.
  18. ^ Lapthorn C, Pullen F, Chowdhry BZ (2013). "Ion mobility spectrometry-mass spectrometry (IMS-MS) of small molecules: separating and assigning structures to ions". Mass Spectrometry Reviews. 32 (1): 43–71. Bibcode:2013MSRv...32...43L. doi:10.1002/mas.21349. PMID 22941854.
  19. ^ Angel LA, Majors LT, Dharmaratne AC, Dass A (August 2010). "Ion mobility mass spectrometry of Au25(SCH2CH2Ph)18 nanoclusters". ACS Nano. 4 (8): 4691–700. doi:10.1021/nn1012447. PMID 20731448.
  20. ^ Kabir KM, Donald WA (December 2017). "Microscale differential ion mobility spectrometry for field deployable chemical analysis". TrAC Trends in Analytical Chemistry. 97: 399–427. doi:10.1016/j.trac.2017.10.011.
  21. ^ a b Wagner ND, Clemmer DE, Russell DH (31 August 2017). "ESI-IM-MS and Collision-Induced Unfolding That Provide Insight into the Linkage-Dependent Interfacial Interactions of Covalently Linked Diubiquitin". Analytical Chemistry. 89 (18): 10094–10103. doi:10.1021/acs.analchem.7b02932. PMID 28841006.
  22. ^ Tian Y, Han L, Buckner AC, Ruotolo BT (27 October 2015). "Collision Induced Unfolding of Intact Antibodies: Rapid Characterization of Disulfide Bonding Patterns, Glycosylation, and Structures". Analytical Chemistry. 87 (22): 11509–11515. doi:10.1021/acs.analchem.5b03291. PMID 26471104.