Detection of intermediates for the Eschweiler–Clarke reaction by liquid-phase reactive desorption electrospray ionizationmass spectrometry

Abstract

Desorption electrospray ionization mass spectrometry (DESI-MS) has been developed dramatically as a powerful tool for the rapid analysis of samples in their native environment. Here a novel application of DESI-MS was demonstrated for direct probing of the reactive intermediates in the liquid-phase Eschweiler–Clarke reaction, a reductive amination reaction whereby a primary (or secondary) amine is successively N-methylated using excess formaldehyde and formic acid. The intermediates ion species of sodiated amino alcohol ([I + Na]⁺) and iminium ([II]⁺), along with the corresponding protonated molecules of amine reactant ([M + H]⁺) and end product ([III + H]⁺), were simultaneously and unambiguously characterized by the positive ion DESI-MS in the native liquid-phase reactive condition. The operating variables were optimized for better analytical performance including the spray solvent composition (such as formic acid concentration, proportion of methanol–water), voltage applied, spray spatial distance and incident angle. The feasibility of the reactive DESI-MS detection of acid–formaldehyde methylations was further validated using amines of a large variety of chemical types (2 primary and 3 secondary amines). Thus, the liquid-phase reactive DESI-MS technique allows the direct analysis of reaction intermediates occurring in complex liquid solutions without sample preparation to provide a valuable insight into chemical reaction mechanisms.