Compact Mass Spectrometry in Monitoring and Optimization of Flow Chemistry

Introduction

Real-time monitoring of reactions is the key capability required to develop flow chemical synthesis. Existing techniques have their own drawbacks. For instance, gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) are time-intensive techniques, whereas lack of specificity, a key capability to gain in-depth insights into reactions, is a drawback in the case of infrared (IR) and near-infrared (NIR) techniques. This article describes two different reactions in the field of flow chemical synthesis, studied at Leeds University in conjunction with Durham University. The expression compact mass spectrometer (CMS) from Advion was used for both experiments (Figure 1).

Figure 1. Advion’s expression CMS single quadrupole mass spectrometer IMAGE is warped

Experimental Procedure

The two instrument set-ups used in these experiments were slightly different from each other. The first set-up used a syringe to infuse the reaction mixture into the expression CMS through a value, as shown in Figure 2. The second set-up used a syringe pump system for reagent transport into a cell and a valve for automatic transmission of the sample into the CMS, as shown in Figure 3. A reaction optimization and data processing software suite was used to analyze the data provided by the CMS.

Experimental set-up I

Figure 2. Experimental set-up I

Experimental set-up II

Figure 3. Experimental set-up II

The experimental conditions are listed in the following table:

Range

m/z 100 - m/z 800

Scan time

400ms

Scan Speed

1750m/z units/sec

Mobile phase

50% MeCN, 50% H2O (0.1% HCOOH)

Flow rate

0.2mL/min

Source

ESI

Capillary temp

200ºC

Capillary Voltage

80V

Source offset

20

Source span

30

Source gas temp

250ºC

ESI voltage

3500

Polarity

Positive

Experimental Results

The two reactions studied were anomeric deacetylation and deprotection of triacetate (Figure 4). The study results are illustrated in Figure 5.

The two reactions

Figure 4. The two reactions

Figure 5 illustrates the results of the real-time monitoring of the anomeric deacetylation reaction, showing simultaneous decrease in raw materials and increase in final products. The CMS reveals the presence of impurities and intermediates yields useful data pertaining to the reactions, which is often not possible with other techniques. Using this data, chemists gain meaningful information about the reactions and processes leading to better decision-making.

The results of real-time monitoring of the two reactions

The results of real-time monitoring of the two reactions

The results of real-time monitoring of the two reactions

Figure 5. The results of real-time monitoring of the two reactions

The ability to obtain comprehensive data about a reaction helps to understand how the reaction progresses. This, in turn, allows further optimization, important to process development, as well as improves mechanistic understanding of a reaction, which is useful in further development of chemistries.

Close monitoring of the reaction is possible when it is analyzed in the flow cell at different residence times, using MS. As a result, it is possible to observe the conditions that led to the formation of impurities and intermediates in large amounts. This, in turn, helps selecting the optimum residence time. The involvement of two different intermediates for the reaction to progress necessitates proper control and optimization of the reaction so that the intermediates will not be converted as impurities.

In these studies, the flow chemistry equipment is programmed to perform automatic analysis of the reagent ratio in order to provide the reaction mixture at different compositions. The MS analysis generates the profiles of reagent, intermediates, and products. The reaction is optimized using these profiles.

Conclusion

The results presented in this article demonstrate the advantages of integrating the expression CMS into flow chemistry systems. Through a unique flexibility of introduction techniques, reactions can be extensively analyzed in real time, unlike other analytical methods, such as UV, IR/NIR, NMR, and chromatography. The ESI and APCI source options allow monitoring a wide range of reactions.

About Advion, Inc.

Advion develops, manufactures and globally supports mass spectrometers, chip-based ion sources, microfluidic flow chemistry systems and consumables for life science and related industries. We seek to enhance analysis performance and workflows. Using our deep scientific and engineering knowledge of mass spectrometry and microfluidics, we leverage our passionate employees’ commitment to create quality, flexible and fit-for-purpose solutions. More about Advion, Inc. can be found on our website, www.advion.com.


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Last updated: Oct 17, 2019 at 10:19 AM

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