Multivariate analysis of inline benchtop NMR data enables rapid optimization of a complex nitration in flow

Abstract

Inline benchtop NMR analysis is established as a powerful tool for reaction monitoring, but its capabilities are somewhat limited by low spectral resolution, often leading to overlapping peaks and difficulties in quantification. Using a multivariate analysis (MVA) statistical approach to data processing these hurdles can be overcome, enabling accurate quantification of complex product mixtures. By employing rapid data acquisition (2.0 s recording time per spectrum), we demonstrate the use of inline benchtop NMR to guide the optimization of a complex nitration reaction in flow. Accurate quantification of four overlapping species was possible, enabling generation of a robust DoE model along with accurate evaluation of dynamic experiments.

Advanced Real‐Time Process Analytics for Multistep Synthesis in Continuous Flow**

“…Initial work was conducted using the highly reactive salicylic acid, but this gave poor regioselectivity and significant overreaction was observed [20] . To combat this issue, we replaced the starting material with 2ClBA and added a hydrolysis (Figure 1 a).…”

Advanced Real‐Time Process Analytics for Multistep Synthesis in Continuous Flow**

“…Here, a spectrum was acquired every 15 s and the data was processed using a partial least squares (PLS) regression model (Figure 5 b). [20] This model was selected instead of an IHM in this case, due to better performance, but was also set up and processed in real time using PEAXACT software.…”

“…Shims were performed with the flow cell filled with either reaction mixture or an aqueous 0.5 M NaOH solution and referenced to the water peak at 5.00 ppm. Typically, a "QUICKSHIM: ALL" was performed in the Spinsolve software (Magritek) and shim values were below 0.4 Hz linewidth at 50%, below 7.5 Hz linewidth at 0.55% and a signal to noise ratio above 20,000.…”

“…[19] Initial work was conducted using the highly reactive salicylic acid, but this gave poor regioselectivity and significant overreaction was observed. [20] To combat this issue,w e replaced the starting material with 2ClBA and added ah ydrolysis (Figure 1a). Due to the high viscosity of the sulfuric acid solvent and relatively low flow rates ( % 1mLmin À1 combined) as plit-and-recombine type mixer (Ehrfeld, Cascade mixer) was utilized to achieve sufficient mixing for effective reaction (Figure 2a).…”

An automated flow platform for accurate determination of gas–liquid–solid reaction kinetics

“…The approach has been applied to several studies of homogeneous reactions. [26][27][28][29][30][31] Herein we considered its extension to a gas-liquid-solid system with the complex hydrodynamics and transport of multiphase flows. 11,[32][33][34][35] Whenever the gas and liquid flow rates are changed, the hydrodynamics especially for the liquid holdup 36 and mass transfer 37 change accordingly, which is often difficult to describe with an accurate mathematical model.…”