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

• Published in: Journal of flow chemistry Vol. 12; no. 2; pp. 175 - 184
• Main Authors: Hadavi, Darya, Han, Peiliang, Honing, Maarten
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.06.2022
• Subjects: Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Green Chemistry; Industrial Chemistry/Chemical Engineering; Inorganic Chemistry; Nanochemistry; Organic Chemistry; Hetero-Diels Alder reaction; Flow reaction; Tandem mass spectrometry; Ion mobility spectrometry; Annotating ion mobility spectrum; Atmospheric pressure photo ionization
• ISSN: 2062-249X; 2063-0212
• DOI: 10.1007/s41981-021-00209-7

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. Article Highlights Direct connection of a microflow reactor to the ion mobility-mass spectrometry and tandem mass spectrometry analytical technique and data comparison with the batch chemistry. On-line monitoring of the hetero-Diels Alder reaction and analysis of the reaction mechanism and elements. Annotating the ion mobility peaks without the standard molecules