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. 2022 Nov 2;33(11):2120-2128.
doi: 10.1021/jasms.2c00210. Epub 2022 Oct 21.

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

Yuxue Liang  1 , Yamil Simón-Manso  1 , Pedatsur Neta  1 , Stephen E Stein  1
Affiliations

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

Yuxue Liang et al. J Am Soc Mass Spectrom. .

Abstract

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, 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.

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Figures

Figure 1.
Figure 1.
a) Tandem mass spectrum of deprotonated 2-anilinoethanol 1 (ion trap, precursor m/z 136, top), b) Tandem mass spectrum of deprotonated 2-(N-methylanilino)ethanol 2 (ion trap, precursor m/z 150, bottom).
Figure 2.
Figure 2.
Tandem mass spectrum of deprotonated 2-(N-methylanilino)ethanol-18O 2a (ion trap, precursor m/z 152)
Figure 3.
Figure 3.
Tandem mass spectrum of deprotonated 4-(4-morpholinyl)benzoic acid (HCD, normalized collision energy (NCE) at 27, precursor m/z 206).
Figure 4.
Figure 4.
Relative peak intensities as a function of normalized collision energy in the HCD tandem mass spectrum of deprotonated 2-fluoro-4-(4-morpholinyl)benzoic acid 8 on the orbitrap instrument. Intensities are normalized to totalion current. Each curve is identified by the m/z value of the corresponding production (m/z 224 is the precursor ion). Notice that the y-axis is truncated and the scale from 0.0 to 0.2 units of relative intensity is exaggerated on purpose to show the maximum of the peak at m/z 180 (loss of CO2).
Figure 5.
Figure 5.
Oxazolidine-type transition state structure of compound 3 leading to the formation of de-protonated 1,3-dihydro-1-ethyl-2H-azepin-2-one and ethene.
Figure 6.
Figure 6.
Proposed reaction mechanism for the Smiles rearrangement reaction of 4-(4-morpholinyl)benzoic acid 7 based on DFT calculations. The loss of carbon dioxide is not shown. The plot was drawn using Angnes, R. A. mechaSVG, GitHub repository, 2020, doi: 10.5281/zenodo.4065333.
Scheme 1.
Scheme 1.
Classic Smiles rearrangement.
Scheme 2.
Scheme 2.
Structures of 2-anilinoethanol, 4-(4-morpholinyl)benzoic acid and their derivatives
Scheme 3.
Scheme 3.
Synthesis of 2-(N-methylanilino)ethanol-18O
Scheme 4.
Scheme 4.
Proposed nitrogen-oxygen Smiles rearrangement mechanism for the formation of the phenoxideion at m/z 93.
Scheme 5.
Scheme 5.
Proposed nitrogen-oxygen Smiles rearrangement mechanism for fragmentation of deprotonated 4-(4-morpholinyl)benzoic acid.
Scheme 6.
Scheme 6.
Structures of 1-(2-hydroxy-4-morpholinophenyl)ethenone, 12 and 2-morpholino-5,6,7,8-tetrahydroquinazolin-4(3H)-one, 13
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References

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