Nicolai Zientek

Simultaneous (19)F-(1)H medium resolution NMR spectroscopy for online reaction monitoring.

Medium resolution nuclear magnetic resonance (MR-NMR) spectroscopy is currently a fast developing field, which has an enormous potential to become an important analytical tool for reaction monitoring, in hyphenated techniques, and for systematic investigations of complex mixtures. The recent developments of innovative MR-NMR spectrometers are therefore remarkable due to their possible applications in quality control, education, and process monitoring. MR-NMR spectroscopy can beneficially be applied for fast, non-invasive, and volume integrating analyses under rough environmental conditions. Within this study, a simple 1/16″ fluorinated ethylene propylene (FEP) tube with an ID of 0.04″ (1.02mm) was used as a flow cell in combination with a 5mm glass Dewar tube inserted into a benchtop MR-NMR spectrometer with a 1H Larmor frequency of 43.32MHz and 40.68MHz for 19F. For the first time, quasi-simultaneous proton and fluorine NMR spectra were recorded with a series of alternating 19F and 1H single scan spectra along the reaction time coordinate of a homogeneously catalysed esterification model reaction containing fluorinated compounds. The results were compared to quantitative NMR spectra from a hyphenated 500MHz online NMR instrument for validation. Automation of handling, pre-processing, and analysis of NMR data becomes increasingly important for process monitoring applications of online NMR spectroscopy and for its technical and practical acceptance. Thus, NMR spectra were automatically baseline corrected and phased using the minimum entropy method. Data analysis schemes were designed such that they are based on simple direct integration or first principle line fitting, with the aim that the analysis directly revealed molar concentrations from the spectra. Finally, the performance of 1/16″ FEP tube set-up with an ID of 1.02mm was characterised regarding the limit of detection (LOQ (1H)=0.335molL-1 and LOQ (19F)=0.130molL-1 for trifluoroethanol in D2O (single scan)) and maximum quantitative flow rates up to 0.3mLmin-1. Thus, a series of single scan 19F and 1H NMR spectra acquired with this simple set-up already presents a valuable basis for quantitative reaction monitoring.

Automated data evaluation and modelling of simultaneous 19F–1H medium-resolution NMR spectra for online reaction monitoring

Medium‐resolution nuclear magnetic resonance spectroscopy (MR‐NMR) currently develops to an important analytical tool for both quality control and process monitoring. In contrast to high‐resolution online NMR (HR‐NMR), MR‐NMR can be operated under rough environmental conditions. A continuous re‐circulating stream of reaction mixture from the reaction vessel to the NMR spectrometer enables a non‐invasive, volume integrating online analysis of reactants and products. Here, we investigate the esterification of 2,2,2‐trifluoroethanol with acetic acid to 2,2,2‐trifluoroethyl acetate both by 1H HR‐NMR (500 MHz) and 1H and 19F MR‐NMR (43 MHz) as a model system. The parallel online measurement is realised by splitting the flow, which allows the adjustment of quantitative and independent flow rates, both in the HR‐NMR probe as well as in the MR‐NMR probe, in addition to a fast bypass line back to the reactor. One of the fundamental acceptance criteria for online MR‐MNR spectroscopy is a robust data treatment and evaluation strategy with the potential for automation. The MR‐NMR spectra are treated by an automated baseline and phase correction using the minimum entropy method. The evaluation strategies comprise (i) direct integration, (ii) automated line fitting, (iii) indirect hard modelling (IHM) and (iv) partial least squares regression (PLS‐R). To assess the potential of these evaluation strategies for MR‐NMR, prediction results are compared with the line fitting data derived from the quantitative HR‐NMR spectroscopy. Although, superior results are obtained from both IHM and PLS‐R for 1H MR‐NMR, especially the latter demands for elaborate data pretreatment, whereas IHM models needed no previous alignment. Copyright

Quantitative online NMR spectroscopy of technical mixtures: on the fly quantification of fluids

In this paper quantitative NMR spectroscopy is demonstrated as a tool for process analytical technology (PAT) in order to obtain real time information from dynamic processes. Different methods for quantification are presented and as a result the limit of detection for NMR measurement could be determined to 3.3 mg kg−1 (ethanol in water). As model processes esterification reactions and dissolution of pharmaceutical formulations are presented and important process parameters are extracted. Furthermore it is demonstrated that not only 1H-NMR spectroscopy can be used for process monitoring but also 13C-NMR for technical mixtures.