A key factor while developing flow chemical synthesis is the monitoring of reactions in real-time. Using methods such as gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) is time consuming. Likewise, methods such as near-infrared (NIR) and infrared (IR) do not provide the specificity needed to attain comprehensive reaction data.
This article details the research performed at Leeds University along with colleagues from Durham University. The researchers explored flow chemical synthesis using Advion’s expression CMS. Two different reactions were studied (Figure 1).
Figure 1. The two different reactions
Two slightly different set-ups were used for these experiments. The first consisted of a syringe connected to a mass spectrometer. The syringe was used to inject the reaction mixture into the mass spectrometer through a valve (Figure 2). In the second set-up a syringe pump unit was used to transfer reagents into a cell with a valve directing the sample into the mass spectrometer automatically (Figure 3). Data produced in the expression CMS was transmitted into a reaction optimization and data processing software suite.
Figure 2. The first experimental set-up
Figure 3. The second experimental set-up
The key conditions of the experimental set-up are listed below:
||m/z 100 - m/z 800
||50% MeCN, 50% H2O (0.1% HCOOH)
|Source gas temperate
Figure 4 illustrates the data for the anomeric deacetyalation. The figure shows real-time monitoring of the reduction in the form of reducing starting material and increasing product levels. Impurities as well as intermediates are observed, thus providing vital data relating to the reaction. This data gives a better understanding than data provided via other methods. Better understanding helps to optimise reactions which is important for process development. It also offers increased understanding which can further assist in the developming the chemistry further.
Figure 4. The study results
It is possible to closely monitor and analyze the reaction at different residence times in the flow cell using MS. The conditions that cause the formation of impurities/intermediates in large quantities can be allowing the most favorable residence time to be chosen.
This reaction progresses through two different intermediates. Care should be taken to ensure that the reaction is controlled accurately and optimized to prevent the intermediates from becoming impurities.
Therefore, it is crucial that the process is well monitored and understood. Programming the flow chemistry equipment allow automatic evaluation of the ratio of reagents, products and intermediates to give differing reaction mixture compositions. Profiles of reagents, intermediates, and products are generated by MS analysis and can be immediately used to optimise the reaction.
The expression CMS has been demonstrated as a highly suitable mass spectrometer for incorporatipwith flow chemistry systems. The input and output options on the expression CMS provide users with versatile interfacing capability. The APCI and ESI source options help extending a range of reactions to be monitored.
The MS provides comprehensive, real-time data regarding reactions, which are often not possible with other analytical methods, such as NMR, chromatography, IR/ NIR, and UV. Advion has the required expertise to incorporate the CMS into advanced synthetic chemistry solutions.
This information has been sourced, reviewed and adapted from materials provided by Advion.
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