New evidence for H/D scrambling of tryptophan and its analogues in the gas phase

RATIONALE Phenethylamides are a large group of naturally occurring molecules found both in the plant and animal kingdoms. In addition, they are used as intermediates for the synthesis of pharmaceutically important dihydro- and tetrahydroisoquinolines. To enable efficient characterization of this class of molecules, a detailed mass spectrometric fragmentation study of a broad series of analogs was carried out. METHODS The test compounds were synthesized using standard methods for amide bond formation. Low energy high resolution tandem mass spectra were acquired on a hybrid quadrupole/time-of-flight mass spectrometer using positive ion electrospray ionization. RESULTS A total of 26 analogs were investigated in the study. Fragmentation of phenethylamides was found to proceed via intermediate ion-neutral complexes. The complexes can break down via multiple pathways including dissociation, proton transfer, Friedel-Crafts acylation, and single electron transfer. The relative contribution of each of these pathways strongly depends on the structure of the coupling amine and acid. CONCLUSIONS A general scheme for the fragmentation of phenethylamides was developed. This study further extends the knowledge base of the ion-neutral complex by discovering Friedel-Crafts acylation as a novel reaction. The strong influence of minor structural modifications on the fragmentation patterns highlights the importance of testing many analogs in order to fully predict a fragmentation pattern of a particular class of molecules.

Section: Resultssupporting

confidence: 88%

Collision‐induced dissociation of phenethylamides: role of ion‐neutral complexes

Nikolić

Macias

Lankin

et al. 2017

“…According to the literature reports, in the fragmentation of protonated tryptophan, a natural indole derivative with an acyclic amino acid substituent on the C 3 position of the indole core, the hydrogen atoms on the amino nitrogen and those at the C 2 and C 4 positions of the indole core are completely scrambled before fragmentation, which is surprisingly similar to the extraordinary scrambling of amide hydrogen in gaseous protonated peptides and proteins. It is meaningful to demonstrate whether this same phenomenon is present in the fragmentation of protonated cyclic indolyl α‐amino esters.…”

mentioning

confidence: 87%

“…This stereoselective proton transfer process is very similar to those of the reversible intramolecular proton transfers between the amino nitrogen and the C 2 and C 4 positions of the indole core prior to the fragmentation of deuterated tryptophan reported in the literature, which proceed from both faces of the indole ring, i.e., delivery of a deuterium from one face and subsequent loss of a proton from the other, resulting in hydrogen-deuterium scrambling. [22][23][24] Moreover, although the hydrogen atom on the C 4 position of the indole ring has been replaced with a methoxyl, the unlabeled product ion b is exclusively generated for the fragmentation of fully labile H/D-exchanged compound 8 shown in Fig. 1(c), which indicates that the hydrogens of the methoxyl on the C 4 position have participated in the proton transfer reaction.…”

Section: Stereoselective Proton Transfer Reaction In Ion-neutral Complexmentioning

confidence: 99%

Friedel‐Crafts dealkylation reaction mediated by a stereoselective proton transfer in the fragmentation of protonated cyclic indolyl α‐amino esters

Cao

Wang

et al. 2016

Using H/D exchange experiments combined with theoretical calculations, a Friedel-Crafts dealkylation reaction mediated by a stereoselective proton transfer in the [cyclic N-sulfonyl ketimino esters/protonated indoles] complex was proposed for the fragmentation of protonated cyclic indolyl α-amino esters in high-energy collisional dissociation tandem mass spectrometry for the first time. Copyright © 2016 John Wiley & Sons, Ltd.

“…In addition, the H/D scrambling reactions can take place between the deuterium and the hydrogens on the ortho-position of the phenyl ring, [14] and the hydrogens in the methyl linked to the indole ring. [15] As described in Scheme 2, ions A and B result from hydride transfer and direct separation of the intermediate INC-1, respectively, and ions C and D arise from hydride transfer and electron transfer reactions within the intermediate INC-2, respectively. To investigate the influence of the substituents on these two competitive reactions, compounds 2-6 with different substituents at the C2 position were measured (Table 1 …”

Section: Resultsmentioning

confidence: 99%

Two competitive INC‐mediated reactions in the gas‐phase fragmentation of protonated indolyl benzo[b]carbazoles

Zhang

Jiang

Zou

et al. 2016

Mass spectrometry (MS) is commonly used nowadays in the structural analysis of a large variety of compounds, [1][2][3][4][5][6] including drugs, [5,6] metabolites, [3] particles, [1] intermediates, [4] and forensic evidence.[2] However, MS n -based structural elucidation has been challenging due to the widespread rearrangement reactions induced by ion-neutral complexes (INCs), [7][8][9][10] such as proton transfer, [8] electron transfer, [7,8] hydride transfer, [8] electrophilic aromatic substitution, [9] and nucleophilic aromatic substitution, [10] which have attracted the interest of many mass spectrometrists.Benzo [b]carbazoles are widely distributed in alkaloids and pharmaceuticals, which exhibit antitumor and antibiotic activities.[ [11] The direct infusion experiments were performed on a quadrupole time-of-flight (QTOF) mass spectrometer from (Bruker Daltonics, MA, USA) equipped with an ESI interface in positive ion mode. Typical parameters were set in the experiments, and theoretical calculations were performed by the density functional theory (DFT) method.[12] RESULTS AND DISCUSSIONA typical tandem mass spectrum for [1 + H] + at m/z 347 is depicted in Fig. 1(a + , respectively. Another abundant ion at m/z 332 (ion E) is generated by the loss of a methyl radical via the homolytic cleavage of the C2′-C8′ bond (not pursued here).[13] The elemental compositions of these fragment ions have also been confirmed by accurate mass data (Supplementary Table S1, Supporting Information). The potential pathways for generation of ions A, B, C, and D are proposed in Scheme 2.Prior to rationalization of the fragmentation of [1 + H] + , we should first investigate the potential protonation sites of the molecule.[12] The relative energies of the structures with different protonation sites are summarized in Supplementary Table S2 (Supporting Information). From calculation results, the C6 atom, rather than the aromatic amine N5, is the most