Reaction Monitoring Using Benchtop 19F NMR Spectroscopy

Nuclear magnetic resonance (NMR) spectroscopy remains an integral method of analysis for chemists due to its powerful capabilities for both structural elucidation and quantification. With this combination, it allows scientists to implement on-line flow analysis to monitor reactions. A key benefit of this is the ability to monitor the reaction in real-time and allowing for manipulation of the reaction conditions to control the kinetics, yield, scalability, and to maximize the efficiency of a reaction.[1] This real-time monitoring of reaction progress, including speciation, and the ability to modify key parameters on the fly is an important part of  Process Analytical Technology (PAT), an invaluable tool for any industry focused on optimizing processes and minimizing losses and waste. For more information on PAT, please visit our previous blog post.

An important consideration for many when looking into high-field NMR spectroscopy for flow analysis is the cumbersome size and recurring costs of operation for this instrument, which often makes this technique overlooked for on-line analysis. As a result, other techniques such as gas chromatography (GC), high performance liquid chromatography (HPLC) and mass spectrometry (MS) are often implemented. However, due to advancements in benchtop NMR spectroscopy the negative aspects of high-field NMR have been outweighed, making NMR spectroscopy an attractive technique for on-line analysis.[2]

In this blog post, we show an example for on-line flow reaction monitoring via 19F NMR spectroscopy using the NMReady-60, a generic set-up for which is shown here. Following a slightly modified procedure by Zell et al., the esterification reaction of 2,2,2-trifluoroethanol and 4-fluorobenzoic acid (Figure 1) was monitored.[3]

The data collected with the NMReady-60 can be used for both qualitative and quantitative analysis. Figure 2 displays a magnified stacked plot of the entire reaction from beginning to end at four-minute time intervals.

Figure 2. A stacked plot of 19F NMR spectra acquired at four-minute time intervals for the esterification reaction between 2,2,2-trifluoroethanol and 4-fluorobenzoic acid with CDI in acetone.

As illustrated in Figure 2, the reactants (triplet at ‑77.7 ppm) disappear over time, while the products (triplets at ‑74.5 ppm and ‑75 ppm) start to appear over time. Furthermore, Table 1 shows the amount of each species in solution at three separate time intervals (beginning, middle and end), which was determined by the relative integration of the fluorinated species.

Table 1. Reaction progression (%) based on integration areas of fluorinated reactant and products in 19F NMR spectra.

As seen in this experiment, benchtop NMR spectrometers make it possible to monitor reactions in real-time using on-line analysis for a fraction of the costs associated with traditional high field NMR, making it a great alternative to this technique while still offering key structural elucidation and quantification capabilities. For a detailed description of this experiment, please refer to our application note and do not hesitate to ask us if you have any questions!

[1] Gomez, M.; de la Hoz, A. Beilstein J. Org. Chem. 2017, 13, 285-300.
[2] Danieli, E.; Perlo, J.; Duchateau, A.; Verzijl, G.; Litvinov, V.; Blümich, B.; Casanova, F. ChemPhysChem 2014, 15 (14), 3060-3066.
[3] Zell, M.; Marquez, B.; am Ende, D.; Dube, P.; Gorman, E.; Krull, R.; Piroli, D.; Colson, K.; Fey, M. Monitoring Chemical Reactions in Real Time with NMR Spectroscopy http://www.rsc.org/events/download/Document/a60b97ab-0a07-4b7f-8e49-bb7b1ce112ff (Accessed Mar 31, 2020).