Analytische Chemie
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Eingeladener Vortrag
- nein (6)
Data set of low-field NMR spectra of continuous synthesis of nitro-4’-methyldiphenylamine (MNDPA). 1H spectra (43 MHz) were recorded as single scans.
Two different approaches for the generation of artificial neural networks training data for the prediction of reactant concentrations were used: (i) Training data based on combinations of measured pure component spectra and (ii) Training data based on a spectral model.
Synthetic low-field NMR spectra
First 4 columns in MAT-files represent component areas of each reactant within the synthetic mixture spectrum.
Xi (“pure component spectra dataset”)
Xii (“spectral model dataset”)
Experimental low-field NMR spectra from MNDPA-Synthesis
This data set represents low-field NMR-spectra recorded during continuous synthesis of nitro-4’-methyldiphenylamine (MNDPA). Reference values from high-field NMR results are included.
A big problem with the chemistry literature is that it is not standardized with respect to precise operational parameters, and real time corrections are hard to make without expert knowledge. This lack of context means difficult reproducibility because many steps are ambiguous, and hence depend on tacit knowledge. Here we present the integration of online NMR into an automated chemical synthesis machine (CSM aka. “Chemputer” which is capable of small-molecule synthesis using a universal programming language) to allow automated analysis and adjustment of reactions on the fly. The system was validated and benchmarked by using Grignard reactions which were chosen due to their importance in synthesis. The system was monitored in real time using online-NMR, and spectra were measured continuously during the reactions. This shows that the synthesis being done in the Chemputer can be dynamically controlled in response to feedback optimizing the reaction conditions according to the user requirements.
Produzieren Sie schon oder kalibrieren Sie noch? – Online-NMR-Spektrometer als Smarte Feldgeräte
(2018)
Der Vortrag zeigt allgemeine Anforderungen an "smarte Feldgeräte" und deren Entwicklung in den vergangenen Jahren. Am Beispiel eines smarten Online-NMR-Sensors, der in einem EU-Projekt von der BAM entwickelt wurde, wird die Umsetzung der Anforderung aufgezeigt. Schließlich werden weitere Technologieanforderungen und Lösungsansätze vorgestellt.
Modular production involving Benchtop NMR: Current application examples driven by digitalization
(2021)
The demand for increasing product diversity in the chemical and pharmaceutical industry calls for new production processes that enable greater flexibility. Therefore, plants are needed which can be adapted to new processes in a fast manner and be scaled up and down easily to volatile market demands. Modular production techniques in combination with advanced process analytical technology (PAT) are considered as a promising solution able to fulfil these requirements.
The success and acceptance of modular concepts in both new and existing plants is dependent of its reliability, easy applicability, and standardization. In recent past, enormous efforts were made to overcome existing barriers in a superordinate level, e.g. DEXPI [1], ENPRO [2], or MTP [3] naming just a few. Here, we’d like to present a few, more hands-on, application examples which are shown in Figure 1 aiming to increase process flexibility and applicability.
This includes:
a) The development of an additively manufactured mixer—flow reactor combination for the application inside of NMR instruments. [4]
b) The application of automated, model-based approaches for model development and spectra evaluation.
c) The application of machine-assisted spectral model building as a genuine alternative to classical model-based approaches [5]
d) Improvement of NIR calibration through online available NMR reference data. [6]
These examples represent miscellaneous use cases but result of the same fact: the increased use and availability of data through advanced PAT and therefore new opportunities utilizing them.
Modular production involving benchtop NMR Current Application Examples Driven by Digitalization
(2022)
The demand for increasing product diversity in the chemical and pharmaceutical industry calls for new production processes that enable greater flexibility. Therefore, plants are needed which can be adapted to new processes in a fast manner and be scaled up and down easily to volatile market demands. Modular production techniques in combination with advanced process analytical technology (PAT) are considered as a promising solution able to fulfil these requirements.
The success and acceptance of modular concepts in both new and existing plants is dependent of its reliability, easy applicability, and standardization. In recent past, enormous efforts were made to overcome existing barriers in a superordinate level, e.g. DEXPI, ENPRO, or MTP naming just a few. Here, we’d like to present a few, more hands-on, application examples which are shown in Figure 1 aiming to increase process flexibility and applicability.
Modular production involving benchtop NMR Current Application Examples Driven by Digitalization
(2022)
The demand for increasing product diversity in the chemical and pharmaceutical industry calls for new production processes that enable greater flexibility. Therefore, plants are needed which can be adapted to new processes in a fast manner and be scaled up and down easily to volatile market demands. Modular production techniques in combination with advanced process analytical technology (PAT) are considered as a promising solution able to fulfil these requirements.
The success and acceptance of modular concepts in both new and existing plants is dependent of its reliability, easy applicability, and standardization. In recent past, enormous efforts were made to overcome existing barriers in a superordinate level, e.g. DEXPI, ENPRO, or MTP naming just a few. Here, we’d like to present a few, more hands-on, application examples which are shown in Figure 1 aiming to increase process flexibility and applicability.
Intensified continuous processes are in focus of current research. Compared to traditional batch processes, intensified continuous production allows the synthesis of new and difficult producible compounds with better product uniformity and reduced consumption of raw materials and energy. Flexible (modular) chemical plants can produce various products using the same equipment with short down-times between campaigns, and quick introduction of new products to the market. Consequently, the demand for powerful Process Analytical Technologies, which can monitor key variables like component concentrations in real-time, is increasing. Low-Field NMR spectroscopy presents itself as such an upcoming smart sensor1,2 (as addressed, e.g., in the CONSENS project3,4).
Continuous measurement approaches can usually be differed in On- or In-line which both have advantages and drawbacks. On the one hand On-line measurements are easy to integrate even in existing setups through bypass systems, on the other hand issues like the representativity of the sampling must be considered. In the case of Inline analysis, where the whole fluid stream is analyzed, this issue can be avoided. Nevertheless, homogeneity of the mixture must be assured using NMR spectroscopy.
This talk shall give a brief summary of current Online and Inline Low-Field NMR approaches. Furthermore, current research results using a tailor-made flow cell for inline analysis are shown pointing out the working range as well as limitations of these method in combination with NMR spectroscopy.
Intensified continuous processes are in focus of current research. Compared to traditional batch processes, intensified continuous production allows the synthesis of new and difficult producible compounds with better product uniformity and reduced consumption of raw materials and energy. Flexible (modular) chemical plants can produce various products using the same equipment with short down-times between campaigns, and quick introduction of new products to the market.
Full automation is a prerequisite to realize such benefits of intensified continuous plants. In continuous flow processes, continuous, automated measurements and closed-loop control of the product quality are required. Consequently, the demand for smart sensors, which can monitor key variables like component concentrations in real-time, is increasing. Low-Field NMR spectroscopy presents itself as such an upcoming smart sensor (as addressed, e.g., in the CONSENS project1,2).
Systems utilizing such an online NMR analyzer benefits through short development and set-up times when applied to modular production plants starting from a desired chemical reaction. As an example for such a modular process unit, we present the design and validation of an integrated NMR micro mixer based on computational modelling suited for a desired chemical reaction. This method includes a proper design of a continuous reactor, which is optimized through computational fluid dynamics (CFD) for the demands of the NMR sensor as well as for the given reaction conditions. The system was validated with a chemical reaction process.
There have been an increasing number of publications on flow chemistry applications of compact NMR. Despite this, there is so far no comprehensive workflow for the technical design of flow cells. Here, we present an approach that is suitable for the design of an NMR flow cell with an integrated static mixing unit. This design moves the mixing of reactants to the active NMR detection region within the NMR instrument, presenting a feature that analyses chemical reactions faster (5–120 s region) than other common setups. During the design phase, the targeted mixing homogeneity of the components was evaluated for different types of mixing units based on CFD simulation. Subsequently, the flow cell was additively manufactured from ceramic material and metal tubing. Within the targeted working mass flow range, excellent mixing properties as well as narrow line widths were confirmed in validation experiments, comparable to common glass tubes.
The application of compact NMR instruments to hot flowing samples or exothermically reacting mixtures is limited by the temperature sensitivity of permanent magnets. Typically, such temperature effects directly influence the achievable magnetic field homogeneity and hence measurement quality. The internal-temperature control loop of the magnet and instruments is not designed for such temperature compensation. Passive insulation is restricted by the small dimensions within the magnet borehole. Here, we present a design approach for active heat shielding with the aim of variable temperature control of NMR samples for benchtop NMR instruments using a compressed airstream which is variable in flow and temperature. Based on the system identification and surface temperature measurements through thermography, a model predictive control was set up to minimise any disturbance effect on the permanent magnet from the probe or sample temperature. This methodology will facilitate the application of variable-temperature shielding and, therefore, extend the application of compact NMR instruments to flowing sample temperatures that differ from the magnet temperature.