In Situ Reaction Monitoring of Unstable Lithiated Intermediates through Inline FTIR Spectroscopy

Fath, Verena; Kockmann, Norbert; Röder, Thorsten

doi:10.1002/ceat.201900074

Cited by 11 publications

(37 citation statements)

References 58 publications

(83 reference statements)

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“…In a first step, the exothermic deprotonation reaction of a CHacidic compound 1 in tetrahydrofuran THF (anhydrous max. 0.005% H 2 O, Merck, Germany) with n-butyllithium 2 leads to a non-isolable, unstable, lithiated intermediate compound 3 [55][56][57]. This deprotonation step is followed by a nucleophilic addition including the lithiated intermediate's reaction with an electrophilic compound 4.…”

Section: Organometallic Synthesismentioning

confidence: 99%

“…As the kinetics of the deprotonation step had already been studied in detail [55][56][57], deprotonation of the CH-acidic compound 1 was performed at a constant residence time of 8 min and a temperature of −35°C, ensuring full conversion of the nbutyllithium 2. In order to avoid clogging, the CH-acidic compound 1 was provided in marginal excess; the stoichiometric ratio of n-butyllithium: CH-acidic compound amounted to 0.8.…”

Section: Microreactor Experimentsmentioning

confidence: 99%

“…Unlike prior works (e.g., [23,28,[52][53][54]), chromatographic separation had not been conducted before MS The use of an inline FT-IR spectrometer (Bruker ALPHA, United States) allowed for real-time reaction tracking with time delay <1 s, circumventing the need to quench the reaction. The reactor outlet was directly connected to the spectrometer's flow cell through a very short capillary of 3 cm with an inner diameter of 0.5 mm [55]. The measuring cell of the FT-IR spectrometer with a volume of 40 μL enabled extremely fast measurement times, shorter than 2 ms (flow rates ≥0.31 mL min −1 ).…”

Section: Inline Ft-ir and Online Ms Measurementsmentioning

confidence: 99%

“…In the second study, the estimated product yield from FT-IR analysis was combined with information from MS analysis aiming at maximising product yield and purity. The organometallic synthesis with n-butyllithium was used as proof of concept, as kinetics and mechanism had already been studied in detail [55][56][57]74]. Pure substances of all involved compounds were available meaning that calibration curves, and thus reference values, had already been known in advance.…”

Section: Organometallic Synthesismentioning

confidence: 99%

“…The high flexibility of the chosen set-up is demonstrated by means of optimisation of two different reaction types that are of great industrial significance, namely an organometallic reaction with n-butyllithium [55][56][57] and an epoxide synthesis [58]. Both studied reactions serve as starting points for a multitude of further synthesis steps.…”

Section: Introductionmentioning

confidence: 99%

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Simultaneous self-optimisation of yield and purity through successive combination of inline FT-IR spectroscopy and online mass spectrometry in flow reactions

et al. 2021

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Self-optimisation constitutes a very helpful tool for chemical process development, both in lab and in industrial applications. However, research on the application of model-free autonomous optimisation strategies (based on experimental investigation) for complex reactions of high industrial significance, which involve considerable intermediate and by-product formation, is still in an early stage. This article describes the development of an enhanced autonomous microfluidic reactor platform for organolithium and epoxide reactions that incorporates a successive combination of inline FT-IR spectrometer and online mass spectrometer. Experimental data is collected in real-time and used as feedback for the optimisation algorithms (modified Simplex algorithm and Design of Experiments) without time delay. An efficient approach to handle intricate optimisation problems is presented, where the inline FT-IR measurements are used to monitor the reaction’s main components, whereas the mass spectrometer’s high sensitivity permits insights into the formation of by-products. To demonstrate the platform’s flexibility, optimal reaction conditions of two organic syntheses are identified. Both pose several challenges, as complex reaction mechanisms are involved, leading to a large number of variable parameters, and a considerable amount of by-products is generated under non-ideal process conditions. Through multidimensional real-time optimisation, the platform supersedes labor- and cost-intensive work-up procedures, while diminishing waste generation, too. Thus, it renders production processes more efficient and contributes to their overall sustainability. Graphical abstract

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Section: Organometallic Synthesismentioning

confidence: 99%

Section: Microreactor Experimentsmentioning

confidence: 99%

Section: Inline Ft-ir and Online Ms Measurementsmentioning

confidence: 99%

Section: Organometallic Synthesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Simultaneous self-optimisation of yield and purity through successive combination of inline FT-IR spectroscopy and online mass spectrometry in flow reactions

et al. 2021

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Flowmicro In‐Line Analysis‐Driven Design of Reactions Mediated by Unstable Intermediates: Flash Monitoring Approach

Ashikari,

Yoshioka,

Yonekura

et al. 2024

Chemistry A European J

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The direct observation of reactive intermediates is an important issue for organic synthesis. However, intermediates with an extreme instability are hard to be monitored by common spectroscopic methods such as FTIR. We have developed synthetic method utilizing flow microreactors, which enables a generation and reactions of unstable intermediates. Herein we report that, based on our flowmicro techniques, we developed an in‐line analysis method for reactive intermediates in increments of milliseconds. We demonstrated the direct observation of the living and dead species of the anionic polymerization of alkyl methacrylates. The direct information of the living species enabled the anionic polymerization and copolymerization of oligo(ethylene glycol) methyl ether methacrylates, which is the important but difficult reaction in the conventional method.

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Continuous Flow Synthesis of N,O-Dimethyl-N′-nitroisourea Monitored by Inline Fourier Transform Infrared Spectroscopy: Bayesian Optimization and Kinetic Modeling

Guo,

Luo,

Chai

et al. 2024

Ind. Eng. Chem. Res.

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The synthesis of N,O-dimethyl-N′-nitroisourea, crucial intermediates in pesticide manufacturing, was explored through a substitution reaction between O-methyl-N-nitroisourea and methylamine within a novel continuous flow microreactor system, featuring Fourier transform infrared (FTIR) in-line analysis for real-time monitoring. In this paper, the reaction is investigated using two optimization methods: the contemporary machine learning-based Bayesian optimization and the traditional kinetic modeling. Remarkably, both strategies obtained a similar yield of approximately 83% under equivalent reaction parametersspecifically, an initial reactant concentration of 0.2 mol/L, a reaction temperature of 40 °C, a molar ratio of reactants at 5:1, and a residence time of 240 min. The Bayesian optimization method demonstrated a notable efficiency, achieving optimal conditions within a mere 20 experiments, in contrast to the kinetic modeling approach, which required a more laborious effort for model formulation and validation. However, kinetic modeling allows for a more comprehensive understanding of the reaction, and the two optimization methods fully demonstrate their respective strengths and weaknesses. This study not only highlights the potential of integrating advanced machine learning methods into chemical process optimization but also sets the stage for further exploration into efficient, data-driven approaches in chemical synthesis.

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In Situ Reaction Monitoring of Unstable Lithiated Intermediates through Inline FTIR Spectroscopy

Cited by 11 publications

References 58 publications

Simultaneous self-optimisation of yield and purity through successive combination of inline FT-IR spectroscopy and online mass spectrometry in flow reactions

Simultaneous self-optimisation of yield and purity through successive combination of inline FT-IR spectroscopy and online mass spectrometry in flow reactions

Flowmicro In‐Line Analysis‐Driven Design of Reactions Mediated by Unstable Intermediates: Flash Monitoring Approach

Continuous Flow Synthesis of N,O-Dimethyl-N′-nitroisourea Monitored by Inline Fourier Transform Infrared Spectroscopy: Bayesian Optimization and Kinetic Modeling

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