Online low-field NMR spectroscopy for process control of an industrial lithiation reaction—automated data analysis

Abstract

Monitoring specific chemical properties is the key to chemical process control. Today, mainly optical online methods are applied, which require time- and cost-intensive calibration effort. NMR spectroscopy, with its advantage being a direct comparison method without need for calibration, has a high potential for enabling closed-loop process control while exhibiting short set-up times. Compact NMR instruments make NMR spectroscopy accessible in industrial and rough environments for process monitoring and advanced process control strategies. We present a fully automated data analysis approach which is completely based on physically motivated spectral models as first principles information (indirect hard modeling-IHM) and applied it to a given pharmaceutical lithiation reaction in the framework of the European Union's Horizon 2020 project CONSENS. Online low-field NMR (LF NMR) data was analyzed by IHM with low calibration effort, compared to a multivariate PLS-R (partial least squares regression) approach, and both validated using online high-field NMR (HF NMR) spectroscopy. Graphical abstract NMR sensor module for monitoring of the aromatic coupling of 1-fluoro-2-nitrobenzene (FNB) with aniline to 2-nitrodiphenylamine (NDPA) using lithium-bis(trimethylsilyl) amide (Li-HMDS) in continuous operation. Online 43.5 MHz low-field NMR (LF) was compared to 500 MHz high-field NMR spectroscopy (HF) as reference method.

Progress in Low Field Benchtop NMR Spectroscopy in Chemical and Biochemical Analysis

“…19 DNP in compact, LF-NMR analysis has been applied to successfully study numerous processes such 20 as lactate dehydrogenase activity in prostate carcinomas through hyperpolarisation of [1-13 C] pyruvate 21 [22], as well as mouse brain metabolism [23], together with molecular dynamics in block copolymers 22 [24]. In addition to DNP, signal amplification by reversible exchange (SABRE) is considered a rapid 23 and efficient method of NMR hyperpolarisation that can enhance the sensitivity of proton and 24 heteronuclear experiments [25]. SABRE does not require a hydrogenation reaction, and can occur in 25 the liquid state under standard conditions with relatively cheap equipment ( Figure 2); a transition 26 metal ion catalyst is employed to establish the contact between para-H 2 , which is the polarisation 1 source, and nuclei of interest [26].…”

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

“…Most notably, the group of Maiwald has demonstrated a process monitoring strategy of an S N Ar reaction using inline NMR, quantified using a multivariate analysis PLS model. 23 This was later expanded to simple optimization experiments to maximize plant throughput. 24 In a related concept, it would be of substantial benefit to expand the usage of this techniques to early-stage reaction optimization studies using common approaches, such as DoE or dynamic experimentation.…”

Application of green analytical chemistry to a green chemistry process: Magnetic resonance and Raman spectroscopic process monitoring of continuous ethanolic fermentation

“…The dimensions of the analyzers should follow an ecological and economical point of view (Pinto, Pereira, Ribeiro, & Farinas, ; Pinto, Ribeiro, & Farinas, ). Compact spectrometers, that is, small‐dimension analyzers, are flexible, robust and today available for a wide range of applications (Blümich, ; Blümich & Singh, ; Danieli et al, ; Kern et al, ; Killner, Garro Linck, Danieli, Rohwedder, & Blümich, ; Kreyenschulte, Paciok, Regestein, Blümich, & Büchs, ; Meyer, Kern, Zientek, Guthausen, & Maiwald, ; Singh, Danieli, & Blümich, ). Automated analyses should be performed preferably without sample preparation and in real time (Maiwald et al, ; Meyer et al, ; Rathore, Bhushan, & Hadpe, ; Rosas, Blanco, González, & Alcalà, ; Singh et al, ; Sugimoto, Fukuyama, Sumino, Takagi, & Ryu, ).…”

“…They proved highly flexible and robust. The disadvantage of the somewhat lower resolution of these analyzers has been effectively compensated for by the use of multivariate data analysis (Kern et al, 2018;Šahnić et al, 2016). While some processes have been conducted within a spectrometer's sample cell, vibrational spectrometers have been coupled via flow-cells or probes (Legner, Wirtz, & Jaeger, 2018;Schalk et al, 2017).…”