Mass Spectrometry Based Approach for Organic Synthesis Monitoring

Abstract

Current mass spectrometry-based methodologies for synthetic organic reaction monitoring largely use electrospray ionization (ESI), or other related atmospheric pressure ionizationbased approaches. Monitoring of complex, heterogeneous systems may be problematic because of sampling hardware limitations, and many relevant analytes (neutrals) exhibit poor ESI performance. An alternative monitoring strategy addressing this significant impasse is condensed phase membrane introduction mass spectrometry using liquid electron ionization (CP-MIMS-LEI). In CP-MIMS, a semipermeable silicone membrane selects hydrophobic neutral analytes, rejecting particulates and charged chemical components. Analytes partition through the membrane, and are then transported to the LEI interface for sequential nebulization, vaporization, and ionization. CP-MIMS and LEI are both ideal for continuous monitoring applications of hydrophobic neutral molecules. We demonstrate quantitative reaction monitoring of harsh, complex reaction mixtures (alkaline, acidic, heterogeneous) in protic and aprotic organic solvents. Also presented are solvent-membrane compatibility investigations and, in situ quantitative monitoring of catalytic oxidation and alkylation reactions.

Analysis of impurities in pharmaceuticals by LC‐MS with cold electron ionization

“…17,18 Cappiello and coworkers presented several generations and versions of this type of instrument and utilized it in a range of applications. [19][20][21][22][23][24] This technology was also used by Gill and coworkers. 24 Recently, Mondello and coworkers also had begun working on EI-LC-MS applications.…”

“…Later, the idea of EI‐LC‐MS was developed by several groups 17,18 . Cappiello and coworkers presented several generations and versions of this type of instrument and utilized it in a range of applications 19–24 . This technology was also used by Gill and coworkers 24 .…”

Unveiling the mechanism of N‐methylation of indole with dimethylcarbonate using either DABCO or DBU as catalyst

“…Electrospray ionization mass spectrometry (ESI‐MS) monitoring 32–35 has been established as powerful tool to study reaction mechanism due to its ability to provide continuous and in situ snapshots of the changing composition of ionic species present in reaction solutions. ESI has also been able to transfer, with great gentleness, speed, and sensitivity, many ionic reaction intermediates to the gas phase for MS characterization 36–41 . Due to direct and rapid action, ESI has also been efficient in transferring even most short‐lived intermediates to the gas phase for MS(/MS) characterization.…”

“…Due to direct and rapid action, ESI has also been efficient in transferring even most short‐lived intermediates to the gas phase for MS(/MS) characterization. Many organic reactions or the action of different metal catalysis have been therefore extensively investigated via ESI‐MS allowing “ion fishing” 36–41 of multiple intermediates and products 17,42,43 …”

“…ESI has also been able to transfer, with great gentleness, speed, and sensitivity, many ionic reaction intermediates to the gas phase for MS characterization. [36][37][38][39][40][41] Due to direct and rapid action, ESI has also been efficient in transferring even most shortlived intermediates to the gas phase for MS(/MS) characterization.…”