Using tandem mass spectrometry to predict chemical transformations of 2-pyrimidinyloxy-N-arylbenzyl amine derivatives in solution

Abstract

Tandem mass spectrometry is used to predict the chemical transformations of 2-pyrimidinyloxy-N-arylbenzyl amine derivatives. Compound 1, N-2-2-4,6-dimethoxypyrimidin-2-yloxy benzylamino phenyl benzamide was selected as a model to present our idea. The CID reactions of protonated 1 include an intramolecular S N 2 reaction and a cyclodehydration reaction. Under in-source CID conditions, deprotonated 1 undergoes a Smiles rearrangement reaction and then dissociates to the ion at m/z 349. Theoretical computations were invoked to shed light on the reaction mechanisms of 1 by the semiempirical PM3 method. These studies of gas-phase reactions show the reactivity of some potential reaction centers in this molecule, which inspired us to explore the solution phase analogous reactions of 1. Further experiments show that 1 has two analogous reactions in acidic solution: the acid-catalyzed cyclodehydration reaction and the acid-catalyzed Smiles rearrangement reaction. Moreover, 1 undergoes the base-catalyzed Smiles rearrangement under basic conditions. The present study demonstrates that mass spectrometry can play an important role in predicting the chemical solution phase transformations of 2-pyrimidinyloxy-N-arylbenzyl amine derivatives. (J Am Soc Mass Spectrom 2006, 17, 253-263)

Gas-phase smiles rearrangement reactions of deprotonated 2-(4, 6-dimethoxypyrimidin-2-ylsulfanyl)-N-phenylbenzamide and its derivatives in electrospray ionization mass spectrometry

“…However, gas-phase studies on PhO(CH 2 ) n O Ϫ (n ϭ 2-4) carried out by Eichinger et al [14 -16] suggested that the Smiles rearrangement can be initiated upon collisional activation without any electron-withdrawing substituents. More recently, similar rearrangement reactions were also reported by Guo et al in studies on 2-pyrimidinyloxy-N-aryl-benzylamine derivatives [9] and by Wang et al in collision-induced dissociation studies on phenoxy-N-phenylacetamide derivatives [17].…”

“…However, deprotonated molecules of the amide compounds we were interested in may dissociate differently. As a matter of fact, it has already been reported [9] that upon collisional activation, certain deprotonated amides underwent a skeletal rearrangement before the fragmentation. A gas-phase type Smiles rearrangement mechanism was proposed to explain this rearrangement.…”

“…The Smiles rearrangement in the solution phase has been well documented as an aromatic ipso nucleophilic substitution reaction [12,13] as summarized in Scheme 1. The reaction could be simulated by mass spectrometry in the negative-ion mode, since the Smiles rearrangement reaction is known mainly through a base-catalyzed rearrangement mechanism [9]. The nucleophilic attack normally requires an electron-withdrawing group (e.g., nitro, sulfonyl, or halogen) either at the ortho or para position on the aromatic ring.…”

Gas Phase Chemistry of Li+with Amides: the Observation of LiOH Loss in Mass Spectrometry

“…Here we report our studies of the gas phase chemistry of Li + adducts of these compounds upon ESI-MS/MS, and among the fragment ions we observe are those reflecting loss of LiOH. Product ions that reflect the Smiles rearrangement, which has been well documented in the solution phase [46,47] as summarized in Scheme 1, and other fragmentation reactions are also observed. To further examine the elimination of LiOH from Li + adducts of this class of amide-containing compounds, we have also studied spectra obtained from CID of [M + Li] + ions of the simpler compounds N-phenylbenzamide and N-phenylcinnamide.…”

Integration of High Accuracy N-Terminus Identification in Peptide Sequencing and Comparative Protein Analysis Via Isothiocyanate-Based Isotope Labeling Reagent with ESI Ion-trap TOF MS

“…Encouragingly, DMPITC labeled peptide gave rise to a signal with 2.5-3.5 times stronger than unlabeled and PITC labeled peptides at the same molar concentration. All the priorities of DMPITC are attributed to the advanced structure, 4,6-dimethoxy-pyrimidine, which is a medium electron withdrawing group instead of phenyl in PITC [33,34]. 13 C-NMR spectra of DMPITC and PITC revealed that chemical shift of carbon atom (145.0 ppm) located in the isothiocyanate of DMPITC moved to low field with a 9.5 ppm shift compared with that of carbon atom (135.5 ppm) in PITC.…”