Ion mobility spectrometry-tandem mass spectrometry strategies for the on-line monitoring of a continuous microflow reaction

Abstract

Continuous flow chemistry is an efficient, sustainable and green approach for chemical synthesis that surpasses some of the limitations of the traditional batch chemistry. Along with the multiple advantages of a flow reactor, it could be directly connected to the analytical techniques for on-line monitoring of a chemical reaction and ensure the quality by design. Here, we aim to use ion mobility, mass and tandem mass spectrometry (IMS-MS and MS/MS) for the on-line analysis of a pharmaceutically relevant chemical reaction. We carried out a model hetero-Diels Alder reaction in a microflow reactor directly connected to the IMS-MS and MS/MS using either electrospray or atmospheric pressure photo ionization methods. We were able to monitor the reaction mechanism of the Diels Alder reaction and structurally characterize the reaction product and synthesis side-products. The chosen approach enabled identification of two isomers of the main reaction product. A new strategy to annotate the ion mobility spectrum in the absence of standard molecules was introduced and tested for its validity. This was achieved by determining the survival yield of each isomer upon ion mobility separation and density functional theory calculations. This approach was verified by comparing the theoretically driven collision cross section values to the experimental data. In this paper, we demonstrated the potential of combined IMS-MS and MS/MS on-line analysis platform to investigate, monitor and characterize structural isomers in the millisecond time scale.

Technological advances for analyzing the content of organ-on-a-chip by mass spectrometry

“…MS has been coupled with various interfaces such as liquid chromatography (LC-MS), and ion mobility spectrometry (IMS-MS) ( Hadavi et al, 2019 ; Hadavi et al, 2022a ; Hadavi et al, 2022b ), expanding the applicability of this analytical tool. Currently, the LC-MS(/MS) is a widely used technology as it enables the separation and sensitive detection of a wide range of molecules, including potential isomers ( Holčapek et al, 2012 ; Theodoridis et al, 2012 ).…”

An Automated, Highly Selective Reaction Monitoring Instrument Using Molecular Rotational Resonance Spectroscopy

“…15 However, unavoidable process variations can invalidate many of the underlying assumptions of these models to require their continuous and time-consuming maintenance including recalibration. 12 Techniques such as mass spectrometry, 16 nuclear magnetic resonance (NMR), 17 and high-performance liquid chromatography (HPLC) 18 have the capability to directly quantify each of the components in a reaction mixture, giving deeper insight into the reaction process, but each of these has trade-offs. Low-resolution NMR may suffer from solvent and matrix interferences that result in analysis ambiguity.…”