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)-C≡N+H and its canonical form CH(3)-C+=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/6-311+G(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.