Fragmentation (mass spectrometry)

In mass spectrometry, fragmentation is the dissociation of energetically unstable molecular ions formed from passing the molecules in the ionization chamber of a mass spectrometer. The fragments of a molecule cause a unique pattern in the mass spectrum. These reactions are well documented over the decades and fragmentation pattern is useful to determine the molar weight and structural information of the unknown molecule.[1][2]

Mass spectrometry techniques

Fragmentation can occur in the ion source (in-source fragmentation) where it is generally not a desired effect. Ion source conformation is an important criterion in the level of fragmentation observed. Desired fragmentation is made in the collision zone (post-source fragmentation) of a tandem mass spectrometer. It is a part of gas phase ion chemistry. Few different types of mass fragmentation are collision-induced dissociation (CID) through collision with neutral molecule, surface-induced dissociation (SID) using fast moving ions collision with a solid surface, laser induced dissociation which uses laser to induce the ion formation, electron-capture dissociation (ECD) due to capturing of low energy electrons, electron-transfer dissociation (ETD) through electron transfer between ions, negative electron-transfer dissociation (NETD), electron-detachment dissociation (EDD), photodissociation, particularly infrared multiphoton dissociation (IRMPD) using IR radiation for the bombardment and blackbody infrared radiative dissociation (BIRD) which use IR radiation instead of laser, Higher-energy C-trap dissociation (HCD), and charge remote fragmentation.[3] [4] [5]

Fragmentation reactions

Fragmentation is a type of chemical dissociation, in which removal of the electron from molecule result in ionization. Removal of electrons from either sigma bond, pi bond or nonbonding orbitals causes the ionization.[2] That can take place by a process of homolytic cleavage/ homolysis or heterolytic cleavage/ heterolysis of the bond. Relative bond energy and the ability to undergo favorable cyclic transition states affect the fragmentation process. Rules for the basic fragmentation processes are given by Stevenson’s Rule.

Two major categories of bond cleavage patterns are simple bond cleavage reactions and rearrangement reactions.[2]

Simple bond cleavage reactions

Majority of organic compounds undergo simple bond cleavage reactions, in which, direct cleavage of bond take place. Sigma bond cleavage, radical site-initiated fragmentation, and charge site-initiated fragmentation are few types of simple bond cleavage reactions.[2]

Sigma bond cleavage / σ-cleavage

Sigma bond cleavage is most commonly observed in molecules, which can produce stable cations such as saturated alkanes, secondary and tertiary carbocations. This occurs when an alpha electron is removed. The C-C bond elongates and weakens causing fragmentation. Fragmentation at this site produces a charged and a neutral fragment.[2]

Radical site-initiated fragmentation

Sigma bond cleavage also occurs on radical cations remote from the site of ionization. This is commonly observed in alcohols, ethers, ketones, esters, amines, alkenes and aromatic compounds with a carbon attached to ring. The cation has a radical on a heteroatom or an unsaturated functional group. The driving force of fragmentation is the strong tendency of the radical ion for electron pairing. Cleavage occurs when the radical and an odd electron from the bonds adjacent to the radical migrate to form a bond between the alpha carbon and either the heteroatom or the unsaturated functional group. The sigma bond breaks; hence this cleavage is also known as homolytic bond cleavage or α-cleavage.[2]

Charge site-initiated cleavage

The driving force of charge site-initiated fragmentation is the inductive effect of the charge site in radical cations. The electrons from the bond adjacent to the charged-bearing atom migrate to that atom, neutralizing the original charge and causing it to move to a different site. This term is also called inductive cleavage and is an example of heterolytic bond cleavage.[2]

Rearrangement reactions

Rearrangement reactions are fragmentation reactions that form new bonds producing an intermediate structure before cleavage. One of the most studied rearrangement reaction is the McLafferty rearrangement / γ-hydrogen rearrangement. This occurs in the radical cations with unsaturated functional groups, like ketones, aldehydes, carboxylic acids, esters, amides, olefins, phenylalkanes. During this reaction, γ-hydrogen will transfer to the functional group at first and then subsequent α, β-bond cleavage of the intermediate will take place. [2] Other rearrangement reactions include heterocyclic ring fission (HRF), benzofuran forming fission (BFF), quinone methide (QM) fission or Retro Diels-Alder (RDA).[6]

See also


  1. Fred W. McLafferty (1 January 1993). Interpretation of Mass Spectra. University Science Books. ISBN 978-0-935702-25-5.
  2. Dass, Chhabil (2007). Fundamentals of contemporary mass spectrometry ([Online-Ausg.]. ed.). Hoboken, NJ [u.a.]: Wiley. ISBN 978-0-471-68229-5.
  3. Yost, R. A.; Enke, C. G. (1978). "Selected ion fragmentation with a tandem quadrupole mass spectrometer". Journal of the American Chemical Society. 100 (7): 2274–2275. doi:10.1021/ja00475a072.
  4. Lermyte, Frederik; Valkenborg, Dirk; Loo, Joseph A.; Sobott, Frank (2018). "Radical solutions: Principles and application of electron-based dissociation in mass spectrometry-based analysis of protein structure" (PDF). Mass Spectrometry Reviews. 37 (6): 750–771. doi:10.1002/mas.21560. ISSN 1098-2787.
  5. Chen, Xiangfeng; Wang, Ze; Wong, Y.-L. Elaine; Wu, Ri; Zhang, Feng; Chan, T.-W. Dominic (2018). "Electron-ion reaction-based dissociation: A powerful ion activation method for the elucidation of natural product structures". Mass Spectrometry Reviews. 37 (6): 793–810. doi:10.1002/mas.21563. ISSN 1098-2787. PMID 29603345.
  6. Tandem Mass Spectrometry for Sequencing Proanthocyanidins. Hui-Jing Li and Max L. Deinzer, Anal. Chem., 2007, volume 79, pages 1739-1748, doi:10.1021/ac061823v
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