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Unexpected Gas-Phase Nitrogen-Oxygen Smiles Rearrangement: CID of Deprotonated 2-(N-Methylanilino)ethanol and Morpholinylbenzoic Acid Derivatives



Yuxue Liang, Yamil Simon, Pedatsur Neta, Stephen E. Stein


A nitrogen-oxygen Smiles rearrangement was reported to occur after collisional activation of the PhN(R)CH2CH2O- (R = alkyl) anion, which undergoes a five-membered ring rearrangement to form a phenoxide ion C6H5O-. When R = H, such a Smiles rearrangement is unlikely since the negative charge is more favorably located on the nitrogen atom than the oxygen atom, hence alternative neutral losses dominate the fragmentation. For example, collisional activation of deprotonated 2-anilinoethanol (PhN-CH2CH2OH) leads to the formation of an anilide anion (C6H5NH-, m/z 92) rather than a phenoxide ion (C6H5O-, m/z 93.0343). However, when the amino hydrogen of 2-anilinoethanol is substituted by a methyl group, i.e. 2-(N-methylanilino)ethanol (2ME), a Smiles rearrangement does occur, leading to the phenoxide ion, as the negative charge can only reside on the oxygen atom. To confirm the Smiles rearrangement mechanism, 2-(N-methylanilino)ethanol-18O was synthesized and subjected to collisional activation, leading to an intense peak at m/z 95.0385, which corresponds to the 18O phenoxide ion ([C6H518O]-). The abundance of the phenoxide ion is sensitive to substituents on the N atom, as demonstrated by the observation that an ethyl substituent results in the rearrangement ion with a much lower abundance. The nitrogen-oxygen Smiles rearrangement also occurs for various morpholinylbenzoic acid derivatives with a multistep mechanism, where the phenoxide ion is found to be predominantly formed after loss of CO2, proton transfers, breaking of the morpholine ring, and Smiles rearrangement. The Smiles mechanism is also supported by Density Functional Theory calculations and other observations.
Journal of the American Society for Mass Spectrometry


Gas-Phase, Smiles Rearrangement, CID, deprotonated 2-(N-Methylanilino)ethanol, morpholinylbenzoic Acid, analysis, chemical analysis, chemical databases, chemical structure, chemistry, mass spectra, mass spectrometry


Liang, Y. , Simon, Y. , Neta, P. and Stein, S. (2022), Unexpected Gas-Phase Nitrogen-Oxygen Smiles Rearrangement: CID of Deprotonated 2-(N-Methylanilino)ethanol and Morpholinylbenzoic Acid Derivatives, Journal of the American Society for Mass Spectrometry, [online],, (Accessed May 25, 2024)


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Created October 21, 2022, Updated September 11, 2023