Monitoring Suzuki Coupling Reactions with Benchtop NMR

The ability to monitor and follow a chemical reaction allows chemists to study and understand the underlying factors that govern the outcome of a reaction. NMR spectroscopy is well suited for this application due to the quantitative nature of the technique as well as its superior structural elucidation capabilities. With the rise of benchtop NMR spectroscopy leading to greater access to this technique,we have previously demonstrated the use of our instrument for such purposes in both the laboratory and in process analytics. In this example, adapted from a Journal of Chemical Education article recently published by Thananatthanachon and Lecklider,^[1] the nickel catalyzed Suzuki cross-coupling reaction of 1-bromo-4-(trifluoromethyl)benzene (1) and phenylboronic acid (2) to form 4-(trifluoromethyl)biphenyl (3) was monitored by ¹⁹F NMR spectroscopy with the NMReady-60PRO instrument.

Small aliquots of the reaction mixture were sampled at specific time intervals and transferred into an NMR tube. By taking advantage of the ability of the NMReady-60PRO to lock onto a proton signal, workup of the reaction or the use of deuterated solvents were avoided and the reaction mixture was analyzed directly. As seen in Figure 1, two singlets are observed at −63.0 ppm and −62.7 ppm. Consistent with literature data, the signal at −63.0 ppm is attributed to 1 while the signal at −62.7 ppm is assigned to 3.

Figure 1. A series of 19F NMR spectra monitoring the coupling reaction between 1 and 2 to prepare 3.

It is clearly seen that the signal for 1 decrease over time as the reaction proceeds with concomitant increase in the peak for 3. For a more quantitative analysis, the two singlets are integrated and the ratio of the starting material and product are readily determined (table 1).

Table 1. Percentage of Compounds 1 and 3 at different points of the reaction.

By taking advantage of the NMReady-60PRO, the ubiquitous Suzuki cross-coupling reaction can be easily monitored and studied by NMR spectroscopy. More importantly, our instruments are easily converted into an online detector due to their small footprint and light weight. To learn more about our instruments used as a Process Analytical Technology (PAT) tool, please check out our previous blog post on the topic.

References

^[1]Thananatthanachon, T.; Lecklider, M. R. J. Chem. Ed. 2017, 94, 786.