Mass spectrometric investigations of intermediates from organic reactions using electrospray ionization

Abstract

This thesis focuses on strategies for the mechanistic investigation of organic reactions using electrospray mass spectrometry (ESI-MS). The results of mass spectrometric studies on an organocatalytic aldol reaction as well as an oxidative cross-coupling of tetrahydroisoquinoline derivatives (THIQs) are presented.<br /> An L-proline-based, charge-tagged organocatalyst was successfully synthesized. The positive charge is localized on a 1-ethyl-pyridinium-4-phenoxy substituent which binds to the 4-position of the proline scaffold. A significantly increased sensitivity towards ESI-MS is caused by this charge tag, facilitating the detection of both the catalyst molecule itself and any catalyst-derived species of a reacting solution. Using the labelled organocatalyst, the mass spectrometric detection of two previously postulated reaction intermediates of the direct inverse aldol reaction between aldehydes and diethyl ketomalonate was achieved. A setup consisting of several microreactors and syringe pumps enabled the investigation of the reacting solution immediately after mixing substrates and catalyst. This way, the temporal progression of the reaction could be tracked in detail starting from a reaction time of a few seconds.<br /> Since the mass spectrometric investigation of the above-mentioned intermediates by collision-induced fragmentation does not provide reliable indications on their exact chemical structure, the ions were characterized and identified by infrared multiple photon dissociation (IRMPD) in a further study. The intermediate ions were isolated in an ion trap mass spectrometer in the focus of the intense free-electron laser CLIO (Centre Laser Infrarouge d'Orsay) and indirect infrared spectra were derived from their wavelength-dependent fragmentation efficiency. The measurements were performed with the support and expertise of P. Maître and V. Steinmetz. The IRMPD spectra were interpreted with the aid of density functional theory calculations of vibrational frequencies of possible intermediate structures. Based on optimizations and a preselection of input structures, that were carried out in the course of this thesis, detailed calculations were obtained in collaboration with J. Vidic and T. Bredow. The results suggest that the mass spectrometrically isolated intermediate species exhibit an oxazolidinone structure.<br /> Another research project of this thesis is the mechanistic investigation of the CuCl₂-catalyzed oxidative cross-coupling of THIQs with diethylzinc by ESI-MS. A positively charged iminium species, the key intermediate of this reaction, was detected both after conversion with CuCl₂ and after electrochemical oxidation and subsequently converted to the coupling product by addition of ZnEt₂. These findings are not consistent with the involvement of any copper species during the coupling step. Furthermore, a short-lived intermediary aminium radical species was detected. A commercial reactor cell was used for the electrochemical oxidation and also for the acquisition of voltage-dependent ion intensity curves for mass spectrometric (EC-MS) investigation of various THIQ substrates. In addition to EC-MS measurements, cyclovoltammograms of the different THIQ derivatives were recorded. The limited substrate scope of the reaction could be attributed to the insufficient oxidation potential of CuCl₂. The experiments are a good example for the combination of mass spectrometric and cyclovoltammetric methods using EC MS as a suitable alternative to synthetic screening methods.