Gas-phase Meerwein reaction of epoxides with protonated acetonitrile generated by atmospheric pressure ionizations

Abstract

Ethylnitrilium ion can be generated by protonation of acetonitrile (when used as the LC-MS mobile phase) under the conditions of atmospheric pressure ionizations, including electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) as well as atmospheric pressure photoionization (APPI). Ethylnitrilium ion (CH 3 Ϫ C ϵ N ϩ H and its canonical form CH 3 Ϫ C ϩ ϭ NH) is shown to efficiently undergo the gas-phase Meerwein reaction with epoxides. This reaction proceeds by the initial formation of an oxonium ion followed by three-to-five-membered ring expansion via an intramolecular nucleophilic attack to yield the Meerwein reaction products. The density functional theory (DFT) calculations at the B3LYP/6-311ϩG(d,p) level show that the gas-phase Meerwein reaction is thermodynamically favorable. Collision-induced dissociation (CID) of the Meerwein reaction products yields the net oxygen-by-nitrogen replacement of epoxides with a characteristic mass shift of 1 Da, providing evidence for the cyclic nature of the gas-phase Meerwein reaction products. The gas-phase Meerwein reaction offers a novel and fast LC-MS approach for the direct analysis of epoxides that might be of genotoxic concern during drug development. Understanding and utilizing this unique gas-phase ion/molecule reaction, the sensitivity and selectivity for quantitation of epoxides can be enhanced. (J Am Soc Mass Spectrom 2010, 21, 1802-1813) © 2010 American Society for Mass Spectrometry G as-phase ion/molecule reactions are fast, efficient, and highly sensitive to the fine structural variations such as relative positions of functional groups. Their product distributions often provide diagnostic information for structural characterization of both reactant ions and neutral molecules [1][2][3][4]. Ion/ molecule reactions have also contributed significantly to the elucidation of organic reaction mechanisms, helping to bridge the gap between gas-phase ion chemistry and condensed-phase organic chemistry. It also provides access to key properties and intrinsic reactivities of a great variety of solvent-and counterion-free gaseous ions and, as such, constitutes a powerful tool for chemical studies. Many classic organic reactions have been studied in the gas phase using the mass spectrometric methods [5][6][7][8][9][10][11][12][13][14]. Recently, with the advent of electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI), mass spectrometry has been widely used as an analytical tool for the study of atmospheric pressure ion/molecule reactions. These gas-phase reactions can even yield detailed information regarding the individual reaction step of the catalytic cycles, and thus allow the study of transient intermediates that have not been accessible previously by the condensed-phase techniques [15,16].Epoxides are common reagents or key intermediates in a wide variety of synthetically important condensedphase reactions, including asymmetric synthesis via the opening of the oxirane ring [17][18][19]. For example, Meerwein fi...

High‐resolution mass spectrometry and hydrogen/deuterium exchange study of mitorubrin azaphilones and nitrogenized analogues

“…The different members of the mitorubrin family differ by the substituent R group located at the side chain end of the bicyclical core (Scheme a). By reacting with an amino group, a nitrogenized mitorubrin analogue is formed (Scheme b) …”

“…The different members of the mitorubrin family differ by the substituent R group located at the side chain end of the bicyclical core (Scheme 1a). By reacting with an amino group, [8] a nitrogenized mitorubrin analogue is formed (Scheme 1b). [9] Various structural studies of mitorubrins can be found in the literature, [10,11] some of them use mass spectrometry techniques mostly via electrospray ionization (ESI) and time of flight or quadrupole mass analyzers.…”

Investigation and Applications of In-Source Oxidation in Liquid Sampling-Atmospheric Pressure Afterglow Microplasma Ionization (LS-APAG) Source

“…In recent years, numerous plasma-based ionization techniques under atmospheric pressure or ambient conditions [13][14][15][16][17] are emerging as powerful tools for rapid analysis of diverse analytes, which can also employ Breactive^plasma as the ionization reagent to initiate various types of reactions [18][19][20][21], including conventional chemical reactions, electrochemical or photochemical reactions, and gas-phase ion-molecule reactions. In-source oxidation, as a common reaction in the ionization process, should be avoided in routine analysis but has been successfully applied in structural analysis [7].…”

Acetonitrile Adducts of Tranexamic Acid as Sensitive Ions for Quantification at Residue Levels in Human Plasma by UHPLC-MS/MS

“…Both the carboxylic acid and the amine functional groups can attack the electro-deficient carbon atom of the protonated acetonitrile leading to the formation of adducts 7a and/or 7b (Scheme 3). The ethylnitrilium ion can be generated under the conditions of ESI when ACN is used as a component of the LC-MS/MS mobile phase and participates in gas-phase reactions [33]. Considering the formed adduct 7a, it can then rearrange to the corresponding pseudo-molecular ion 1 by loss of a molecule of acetonitrile and further fragmentation results in the formation of product ions 4 and 5 as described above.…”