TY - JOUR A1 - Bornemann-Pfeiffer, Martin A1 - Wolf, Jakob A1 - Meyer, Klas A1 - Kern, S. A1 - Angelone, D. A1 - Leonov, A. A1 - Cronin, L. A1 - Emmerling, Franziska T1 - Standardization and control of Grignard reactions in a universal chemical synthesis machine using online NMR T1 - Standardisierung und Kontrolle von Grignard-Reaktionen mittels Online-NMR in einer universellen chemischen Syntheseplattform N2 - 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. N2 - Ein Problem der chemischen Literatur ist die fehlende Standardisierung bezüglich genauer Bedingungen, auch Echtzeit-Korrekturen sind ohne Expertenwissen nur schwer möglich. Dieser Mangel an Details erschwert experimentelle Reproduzierbarkeit, da Schritte oft mehrdeutig sind und daher von implizitem Wissen abhängen. Hier präsentieren wir die Integration von Online-NMR Spektroskopie in eine automatisierte chemische Syntheseplattform (CSM aka. “Chemputer”, unter Verwendung einer universellen Programmiersprache zur Synthese kleiner Moleküle fähig), um eine automatisierte Analyse und Anpassung von Reaktionen im laufenden Betrieb zu ermöglichen. Das System wurde anhand von Grignard-Reaktionen, die aufgrund ihrer Bedeutung für die Synthese ausgewählt wurden, validiert und einem Härtetest unterzogen. Synthesen wurden in Echtzeit mit Online-NMR überwacht, und die Spektren wurden während der Reaktionen kontinuierlich aufgenommen und analysiert. Dies zeigt, dass der Chemputer dynamisch mittels einer Regelung kontrolliert werden kann, um die Reaktionsbedingungen entsprechend den Anforderungen des Benutzers zu optimieren. KW - Grignard reaction KW - NMR spectroscopy KW - Process analytical technology KW - Process control KW - Grignard-Reaktion KW - NMR-Spektroskopie KW - Prozessanalytik KW - Prozesskontrolle PY - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:b43-531260 SN - 1521-3773 SN - 1433-7851 N1 - Bibliografische Angaben für die deutsche Version: Angewandte Chemie 2021, Jg. 133, S. 1–7, ISSN 0044-8249, ISSN 1521-3757, https://doi.org/10.1002/ange.202106323 - Bibliographic information for the German version: Angewandte Chemie 2021, vol. 133, p. 1–7, ISSN 0044-8249, ISSN 1521-3757, https://doi.org/10.1002/ange.202106323 VL - 60 IS - 43 SP - 1 EP - 6 PB - Wiley-VCH CY - Weinheim AN - OPUS4-53126 LA - mul AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - JOUR A1 - Zientek, Nicolai A1 - Laurain, Clement A1 - Meyer, Klas A1 - Kraume, M. A1 - Guthausen, G. A1 - Maiwald, Michael T1 - Simultaneous 19F-1H medium resolution NMR spectroscopy for online reaction monitoring N2 - 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'' (1.02 mm) was used as a flow cell in combination with a 5 mm glass Dewar tube inserted into a benchtop MR-NMR spectrometer with a 1H Larmor frequency of 43.32 MHz and 40.68 MHz 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 500 MHz 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 1.02 mm was characterised regarding the limit of detection (LOQ (1H) = 0.335 mol L-1 and LOQ (19F) = 0.130 mol L-1 for trifluoroethanol in D2O (single scan)) and maximum quantitative flow rates up to 0.3 mL min-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. KW - NMR KW - 1H KW - 19F KW - Medium-resolution NMR KW - Online NMR KW - Quantitative NMR KW - Reaction monitoring KW - Data processing KW - Process analytical technology PY - 2014 U6 - https://doi.org/10.1016/j.jmr.2014.10.007 SN - 1090-7807 SN - 0022-2364 VL - 249 SP - 53 EP - 62 PB - Elsevier CY - San Diego, Calif. AN - OPUS4-32008 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - JOUR A1 - Zientek, Nicolai A1 - Meyer, Klas A1 - Kern, Simon A1 - Maiwald, Michael T1 - Quantitative online NMR spectroscopy in a nutshell N2 - Online NMR spectroscopy is an excellent tool to study complex reacting multicomponent mixtures and gain process insight and understanding. For online studies under process conditions, flow NMR probes can be used in a wide range of temperature and pressure. This paper compiles the most important aspects towards quantitative process NMR spectroscopy in complex multicomponent mixtures and provides examples. After NMR spectroscopy is introduced as an online method and for technical samples without sample preparation in deuterated solvents, influences of the residence time distribution, pre-magnetization, and cell design are discussed. NMR acquisition and processing parameters as well as data preparation methods are presented and the most practical data analysis strategies are introduced. KW - Prozessanalytik KW - Process analytical technology KW - Online NMR spectroscopy KW - Online monitoring PY - 2016 U6 - https://doi.org/10.1002/cite.201500120 SN - 0009-286X VL - 88 IS - 6 SP - 698 EP - 709 PB - Wiley-VCH Verlag GmbH & Co. KGaA CY - Weinheim, Germany AN - OPUS4-36333 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - JOUR A1 - Meyer, Klas A1 - Rademann, K. A1 - Panne, Ulrich A1 - Maiwald, Michael T1 - Quantitative NMR spectroscopy for gas analysis for production of primary reference gas mixtures N2 - Due to its direct correlation to the number of spins within a sample quantitative NMR spectroscopy (qNMR) is a promising method with absolute comparison abilities in complex systems in technical, as well as metrological applications. Most of the samples studied with qNMR are in liquid state in diluted solutions, while gas-phase applications represent a rarely applied case. Commercially available NMR equipment was used for purity assessment of liquid and liquefied hydrocarbons serving as raw materials for production of primary reference gas standards. Additionally, gas-phase studies were performed within an online NMR flow probe, as well as in a high-pressure NMR setup to check feasibility as verification method for the composition of gas mixtures. KW - Quantitative NMR spectroscopy KW - Gas-phase NMR spectroscopy KW - Primary reference gas mixtures PY - 2017 UR - http://www.sciencedirect.com/science/article/pii/S1090780716302518 U6 - https://doi.org/10.1016/j.jmr.2016.11.016 SN - 1090-7807 SN - 1096-0856 VL - 275 SP - 1 EP - 10 AN - OPUS4-38803 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - JOUR A1 - Tchipilov, Teodor A1 - Meyer, Klas A1 - Weller, Michael G. T1 - Quantitative 1H Nuclear Magnetic Resonance (qNMR) of Aromatic Amino Acids for Protein Quantification N2 - Hydrolysis of protein samples into amino acids facilitates the use of NMR spectroscopy for protein and peptide quantification. Different conditions have been tested for quantifying aromatic amino acids and proteins. The pH-dependent signal shifts in the aromatic region of amino acid samples were examined. A pH of 12 was found to minimize signal overlap of the four aromatic amino acids. Several aromatic compounds, such as terephthalic acid, sulfoisophthalic acid, and benzene tricarboxylic acid, were applied as internal standards. The quantification of amino acids from an amino acid standard was performed. Using the first two suggested internal standards, recovery was ~97% for histidine, phenylalanine, and tyrosine at a concentration of approximately 1 mM in solution. Acidic hydrolysis of a certified reference material (CRM) of bovine serum albumin (BSA) and subsequent quantification of Phe and Tyr yielded recoveries of 98% ± 2% and 88% ± 4%, respectively, at a protein concentration of 16 g/L or 250 µM. KW - Amino acid analysis KW - Aromatic amino acid analysis KW - AAA KW - AAAA KW - Protein hydrolysis KW - Hydrochloric acid KW - Metrology KW - Traceability KW - NIST KW - Reference materials KW - Internal standard KW - Calibration KW - Compound-independent calibration KW - Histidine KW - Tyrosine KW - Tryptophan KW - Phenylalanine KW - Terephthalic acid KW - Benzene-1,3,5-tricarboxylic acid KW - Bovine serum albumin (BSA) KW - Quantitative protein analysis KW - Phenylketonuria PY - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:b43-570943 VL - 6 IS - 1 SP - 1 EP - 13 PB - MDPI CY - Basel, Schweiz AN - OPUS4-57094 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - JOUR A1 - Paul, Andrea A1 - Meyer, Klas A1 - Ruiken, Jan-Paul A1 - Illner, M. A1 - Müller, D.-N. A1 - Esche, E. A1 - Wozny, G. A1 - Westad, Frank A1 - Maiwald, Michael T1 - Process spectroscopy in microemulsions — Raman spectroscopy for online monitoring of a homogeneous hydroformylation process N2 - A major industrial reaction based on homogeneous catalysis is hydroformylation for the production of aldehydes from alkenes and syngas. Hydroformylation in microemulsions, which is currently under investigation at Technische Universität Berlin on a mini-plant scale, was identified as a cost efficient approach which also enhances product selectivity. Herein, we present the application of online Raman spectroscopy on the reaction of 1-dodecene to 1-tridecanal within a microemulsion. To achieve a good representation of the operation range in the mini-plant with regard to concentrations of the reactants a design of experiments was used. Based on initial Raman spectra partial least squares regression (PLSR) models were calibrated for the prediction of 1-dodecene and 1-tridecanal. Limits of predictions arise from nonlinear correlations between Raman intensity and mass fractions of compounds in the microemulsion system. Furthermore, the prediction power of PLSR models becomes limited due to unexpected by-product formation. Application of the lab-scale derived calibration spectra and PLSR models on online spectra from a mini-plant operation yielded promising estimations of 1-tridecanal and acceptable predictions of 1-dodecene mass fractions suggesting Raman spectroscopy as a suitable technique for process analytics in microemulsions. KW - Raman KW - Online KW - Chemometrics KW - Hydroformylation KW - Mini-plant KW - Microemulsion PY - 2017 U6 - https://doi.org/10.1088/1361-6501/aa54f0 SN - 1361-6501 SN - 0957-0233 VL - 28 IS - 3 SP - 035502-1 EP - 035502-11 PB - IOP Publishing Ltd CY - UK AN - OPUS4-39032 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - JOUR A1 - Meyer, Klas A1 - Ruiken, J.-P. A1 - Illner, M. A1 - Paul, Andrea A1 - Müller, D. A1 - Esche, E. A1 - Wozny, G. A1 - Maiwald, Michael T1 - Process spectroscopy in microemulsions - setup and multi-spectral approach for reaction monitoring of a homogeneous hydroformylation process N2 - Reaction monitoring in disperse systems, such as emulsions, is of significant technical importance in various disciplines like biotechnological engineering, chemical industry, food science, and a growing number other technical fields. These systems pose several challenges when it comes to process analytics, such as heterogeneity of mixtures, changes in optical behavior, and low optical activity. Concerning this, online nuclear magnetic resonance (NMR) spectroscopy is a powerful technique for process monitoring in complex reaction mixtures due to its unique direct comparison abilities, while at the same time being non-invasive and independent of optical properties of the sample. In this study the applicability of online-spectroscopic methods on the homogeneously catalyzed hydroformylation system of 1-dodecene to tridecanal is investigated, which is operated in a mini-plant scale at Technische Universität Berlin. The design of a laboratory setup for process-like calibration experiments is presented, including a 500 MHz online NMR spectrometer, a benchtop NMR device with 43 MHz proton frequency as well as two Raman probes and a flow cell assembly for an ultraviolet and visible light (UV/VIS) spectrometer. Results of high-resolution online NMR spectroscopy are shown and technical as well as process-specific problems observed during the measurements are discussed. KW - Online-spectroscopy KW - Quantitative NMR spectroscopy KW - Process analytical technology KW - Microemulsions PY - 2017 U6 - https://doi.org/10.1088/1361-6501/aa54f3 SN - 0957-0233 SN - 1361-6501 VL - 28 IS - 3 SP - 035501-1 EP - 035501-11 PB - IOP Publishing Ltd. AN - OPUS4-39091 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - JOUR A1 - Meyer, Klas A1 - Kern, Simon A1 - Zientek, Nicolai A1 - Guthausen, G. A1 - Maiwald, Michael T1 - Process control with compact NMR N2 - Compact nuclear magnetic resonance (NMR) instruments make NMR spectroscopy and relaxometry accessible in industrial and harsh environments for reaction and process control. An increasing number of applications are reported. To build an interdisciplinary bridge between “process control” and “compact NMR”,we give a short overviewon current developments in the field of process Engineering such as modern process design, integrated processes, intensified processes along with requirements to process control, model based control, or soft sensing. Finally, robust field integration of NMR systems into processes environments, facing explosion protection or Integration into process control systems, are briefly discussed. KW - Prozessanalytik KW - Quantitative NMR-Spektroskopie KW - Industrie 4.0 KW - Reaction monitoring KW - Process control KW - Online NMR spectroscopy KW - Compact NMR PY - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:b43-373562 UR - http://www.sciencedirect.com/science/article/pii/S0165993616300073 SN - 0165-9936 VL - 83 IS - Part A / SI SP - 39 EP - 52 PB - Elsevier AN - OPUS4-37356 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - JOUR A1 - Kern, Simon A1 - Meyer, Klas A1 - Guhl, Svetlana A1 - Gräßer, Patrick A1 - Paul, Andrea A1 - King, R. A1 - Maiwald, Michael T1 - Online low-field NMR spectroscopy for process control of an industrial lithiation reaction—automated data analysis N2 - 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 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 Modelling – 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 analysed 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. KW - Online NMR spectroscopy KW - Process analytical technology KW - Partial Least Squares Regression KW - Indirect Hard Modeling KW - Benchtop NMR Spectroscopy KW - Smart Sensors KW - CONSENS PY - 2018 UR - https://link.springer.com/article/10.1007/s00216-018-1020-z U6 - https://doi.org/10.1007/s00216-018-1020-z SN - 1618-2642 SN - 1618-2650 VL - 410 IS - 14 SP - 3349 EP - 3360 PB - Springer CY - Berlin, Heidelberg AN - OPUS4-44847 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - JOUR A1 - Zientek, Nicolai A1 - Meyer, Klas A1 - Dalitz, F. A1 - Kraume, M. A1 - Guthausen, G. A1 - Maiwald, Michael T1 - Neue Möglichkeiten für die Prozessanalytik mit gekoppelter 1H- und 19F-Medium-Resolution-NMR-Spektroskopie N2 - Die Entwicklung innovativer Medium-Resolution-NMR-Spektrometer eröffnet eine Reihe bemerkenswerter Applikationen für die Qualitätskontrolle, die akademische Ausbildung und die Prozessanalytik. Die Verwendung von Permanentmagneten erlaubt den Einsatz der NMR-Spektroskopie in industriellen Prozessumgebungen. KW - NMR KW - 1H KW - 19F KW - Medium-resolution NMR KW - Online NMR KW - Quantitative NMR KW - Reaction monitoring KW - Data processing KW - Process analytical technology KW - IHM KW - PLS PY - 2014 U6 - https://doi.org/10.1002/cite.201450687 SN - 0009-286X SN - 1522-2640 VL - 86 IS - 9 SP - 1575 PB - Wiley-VCH Verl. CY - Weinheim AN - OPUS4-32560 LA - deu AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER -