Protonated N-alkyl-2-nitroanilines undergo intramolecular oxidation of the alkyl chain upon collisional activation

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Abstract

The collisional activation of protonated N-propyl-2-nitroaniline obtained by electrospray ionization shows two major competitive dissociation pathways: the elimination of the elements of propionic acid, [M+H−C3H6O2]+ to give an m/z 107 ion, and of the elements of ethanol, [M+H−C2H6O]+ to give an m/z 135 ion. The mechanistic study reported here addresses these unusual fragmentations to reveal that both occur via a common intermediate formed by the transfer of an oxygen atom from the nitro group to the first carbon atom of the propyl group, allowing elimination of propionic acid and (H2O + ethene), respectively. The corresponding loss of CH4O does not occur when the propyl group is replaced by an ethyl group, but elimination of the elements of propanol does occur when propyl is replaced by a butyl group. Further, the product ions of m/z 107 and 135 are also formed when the propyl chain is replaced with a hexyl group.

Introduction

Intramolecular oxygen transfer from a nitro group to other parts of the molecule leading to redox reactions mediated by transition metal ions are known to occur in both the solution [1], [2] and gas phase [3]. These oxygen transfers from nitro group are important in synthetic organic chemistry [4] and in biological transformations [5]. Turecek and coworkers used tandem mass spectrometry in combination with density functional theory to study an oxygen-transfer, gas-phase reaction giving the elimination of H2CO3 from an ionized copper complex of nitro tyrosine [3]. The electron-ionization (EI) induced oxygen transfer from a nitro group leading to intramolecular oxidation of sulfur, alkyl or alkenyl groups in aromatic nitro compounds is well established [6], [7]. The intramolecular oxidation involves either the transfer of oxygen atoms from the nitro group to the heteroatom or side chain [6] within the radical cation or the abstraction of hydrogen atoms from the side chain to the nitro group. The process leads to the elimination of small molecules via a process termed as an ortho effect [7]. Such rearrangements are not common for protonated molecules (closed-shell ions) generated by electrospray ionization (ESI) and activated in low-energy collisions, probably owing to the absence of a radical site. Nevertheless, we previously found an example of intramolecular oxidation of a sulfur atom by an adjoining nitro group for the ESI-protonated 2-nitrophenylphenylsulfide, and we characterized the chemical reactions by experiment supported by theoretical calculations [8].

Others showed that the EI-generated radical cation of N-ethyl-2-nitroaniline eliminates a molecule of acetic acid [9], [10], and, to a small extent, a molecule likely to be acetaldehyde. In an analogous manner, the molecular radical cations of propyl and butyl amines fragment via eliminations of propionic acid and butyric acid, respectively. The mechanism suggested for these gas-phase eliminations of the alkyl group attached to the nitrogen as a carboxylic acid, involves the oxidation of the alkyl group by the ortho nitro group. Do these intramolecular oxidation reactions of nitro group, observed for open-shell ions, occur as analogous reactions in closed-shell, [M+H]+ ions generated by ESI? The answer is important because ESI mass spectrometry has now become the method of choice for the analysis of most organic compounds and pharmaceuticals.

We report here an experimental and theoretical investigation of the collision-activated dissociations of the ESI-generated [M+H]+ ions of N-ethyl-2-nitroaniline (1) N-propyl-2-nitroaniline (2), N-butyl-2-nitroaniline (3), N-hexyl-2-nitroaniline (4), and N-butyl-4-chloro-2-nitroaniline (5). The focus is to understand the possibility of intramolecular oxygen transfer reactions by nitro groups, leading to eliminations of alkanoic acids. We augmented the experimental observations by carrying out density function theory (DFT) calculations to explore the mechanism of oxygen transfer.

We are pleased to dedicate this article to the late Nico M.M. Nibbering, a close friend and colleague whose enthusiastic commitment to ion chemistry continues to be inspirational. The dedication of this paper is indeed appropriate because his first published work focused on the role of the nitro group in the McLafferty rearrangement of the nitropropane radical cation [11], a study that was always a source of pride to him. This work shows another property of the nitro group in gas-phase ion chemistry, and we are certain that the unusual rearrangement/oxidation would interest him.

Section snippets

Synthesis

Compounds 1–4 were prepared by treating a solution of 1-fluoro-2-nitrobenzene (1.0 g) in 10 mL 1,4-dioxane with excess (3 mL) of the appropriate alkyl amine at room temperature, analogous to the synthesis of N-(2-nitrophenyl)benzylamine [12]. Compound 5 was synthesized by refluxing 2,4-dichloronitrobenzene (1.0 g) with butyl amine (3 mL) in 1,4-dioxane. The reactions were completed in 2 h, and the mixture was diluted with 50 mL water and extracted with dichloromethane (2 × 50 mL). Dichloromethane was

Mass spectrometry

ESI of N-ethyl-2-nitroaniline (1) showed that the [M+H]+ ion of m/z 167, upon collisional activation dissociated to yield product ions of m/z 107 and less abundant ions of m/z 149 by eliminating species of 60 (C2H4O2) and 18 u (H2O), respectively (Fig. 1). We assigned the elemental compositions of the [M+H]+ and its fragment ions, by repeating the experiments on an instrument capable of high mass resolving power (Table 1) to confirm that the unexpected fragment ion of m/z 107 is formed by the

Conclusion

The [M+H]+ ions of the N-alkyl-2-nitroanilines undergo unusual oxidation reactions of the alkyl side chains as seen in the CAD spectra and confirmed by DFT calculations. Specifically, a shift of the proton of the activated species to the nitro group leads to the intramolecular oxidation of N-alkyl chain with concomitant reduction of the nitro group and elimination of alkanoic acid with the same number of carbon atoms as in the alkyl chain. Furthermore, when the alkyl chain contains more than

Acknowledgements

The authors are thankful to Principal, Sacred Heart College (Autonomous), Thevara, for providing the DFT calculation facility, funded by DST, New Delhi. J. P. is thankful to Biocon Syngene for their support. This research was supported in part by the NIH, NIGMS (Grant No. P41 GM103422).

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