Article
Chemistry, Applied
Desiree M. Dalligos, Michael J. Pilling, Georgios Dimitrakis, Liam T. Ball
Summary: The suitability of broadband dielectric spectroscopy (DS) for in-line reaction monitoring is demonstrated, showing high precision and accuracy in measuring reaction progress. A convenient method for rapidly assessing the applicability of DS to previously untested reactions or processes is also established. DS is seen as a valuable addition to the process chemist's analytical toolbox due to its orthogonality to other spectroscopic methods, low cost, and ease of implementation.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2023)
Article
Chemistry, Multidisciplinary
Tristan Maschmeyer, Lars P. E. Yunker, Jason E. Hein
Summary: This article presents a stopped-flow benchtop NMR system that allows for convenient acquisition of quantitative reaction monitoring data and has been successfully applied to monitor difficult-to-detect model reaction systems.
REACTION CHEMISTRY & ENGINEERING
(2022)
Article
Food Science & Technology
Alper Soyler, Sevil Cikrikci, Cagri Cavdaroglu, Dylan Bouillaud, Jonathan Farjon, Patrick Giraudeau, Mecit H. Oztop
Summary: This study investigated the application of benchtop NMR spectroscopy in analyzing milk in an industrial context, focusing on production quality and product differentiation. Through quantitative online NMR spectroscopy, lactose hydrolysis in milk was tracked and different milk samples were successfully differentiated based on their properties.
LWT-FOOD SCIENCE AND TECHNOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Margherita Bazzoni, Celia Lhoste, Justine Bonnet, Kouakou Eric Konan, Aurelie Bernard, Patrick Giraudeau, Francois-Xavier Felpin, Jean-Nicolas Dumez
Summary: This work demonstrates the online monitoring of a flow photochemical reaction using advanced NMR methods. By analyzing the reaction mixture directly, both 1D and ultrafast 2D experiments provide valuable information, especially for complex molecules. The study highlights the efficiency of ultrafast 2D COSY experiments for real-time monitoring and quantitative analysis, enabling effective screening of reaction conditions.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Chemistry, Analytical
Celia Lhoste, Margherita Bazzoni, Justine Bonnet, Aurelie Bernard, Francois-Xavier Felpin, Patrick Giraudeau, Jean-Nicolas Dumez
Summary: In this study, ultrafast 2D NMR schemes were developed to acquire full spectral width 2D NMR spectra from continuously flowing samples in a short time. By using an interleaved acquisition strategy and an optimized solvent suppression strategy, it was possible to monitor chemical reactions online at high time resolution.
Article
Chemistry, Multidisciplinary
Tristan Maschmeyer, Breanna Conklin, Thomas C. Malig, David J. Russell, Kenji L. Kurita, Jason E. Hein, Jose G. Napolitano
Summary: Nuclear magnetic resonance (NMR) spectroscopy is a powerful analytical technique that provides quantitative and structural information about multiple components in a sample. This study describes a simple and robust method to determine concentration conversion factors using linear regression models in NMR systems, and applies this method to monitor a pharmaceutically relevant amide coupling reaction.
MAGNETIC RESONANCE IN CHEMISTRY
(2023)
Article
Biochemical Research Methods
Bing Wu, Ruud L. E. G. Aspers, Arno P. M. Kentgens, Evan Wenbo Zhao
Summary: By using high-field operando NMR analysis, researchers gained insights into the working mechanisms of RFBs and improved battery performance. However, the high cost and large footprint of the high-field NMR system limited its implementation. As an alternative, they demonstrated an operando NMR study of an RFB using a low-cost and compact 43 MHz benchtop system, obtaining different results from high-field NMR experiments and providing new insights into RFBs. They concluded that the benchtop NMR system has sufficient capabilities for operando studies of RFBs and could be widely applied in flow electrochemistry research.
JOURNAL OF MAGNETIC RESONANCE
(2023)
Article
Chemistry, Applied
Yuma Miyai, Anna Formosa, Cameron Armstrong, Brian Marquardt, Luke Rogers, Thomas Roper
Summary: This study discusses the implementation of PAT for real-time monitoring of intermediate and product concentrations on the PoD system, achieving a RMSEP of 2.2 mg/mL with a relative error of 2.8% for the step 2 FlowIR model and a RMSEP of 0.9 mg/mL with a relative error of 2.8% for the step 5 Raman model. These models were successfully deployed during continuous ciprofloxacin synthesis on the PoD system, demonstrating the capability of real-time prediction using PAT technology.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2021)
Article
Chemistry, Analytical
Yeongseok Chae, Sein Min, Eunjoon Park, Chaiho Lim, Cheol-Hong Cheon, Keunhong Jeong, Kyungwon Kwak, Minhaeng Cho
Summary: The integration of flow cells with NMR and FTIR systems allows for real-time observation of reaction intermediates, offering a valuable tool for elucidating reaction mechanisms and obtaining elusive kinetic data. By combining the sensitivity of IR spectroscopy with the quantitative analysis capabilities of NMR, this approach enables comprehensive evaluation of reaction processes, including potentially hazardous reactions, without direct contact with harmful intermediates.
ANALYTICAL CHEMISTRY
(2021)
Article
Chemistry, Analytical
Celia Lhoste, Margherita Bazzoni, Justine Bonnet, Aurelie Bernard, Francois-Xavier Felpin, Patrick Giraudeau, Jean-Nicolas Dumez
Summary: This article presents a method for rapid acquisition of broadband homonuclear 2D NMR spectra from continuously flowing samples. The use of interleaved acquisition and optimized solvent suppression allows for obtaining full spectra width in a short period of time. This development is important for online monitoring with high time resolution using flow 2D NMR.
Article
Engineering, Multidisciplinary
Yongxing Guo, Minjie Liu, Meifen Jiang, Yuan Tao, Dang Cheng, Fen -Er Chen
Summary: In this study, the nucleobase unit of the antiviral drug remdesivir, 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine, was synthesized through a five-step continuous flow process. The synthesis was carried out from a readily available and inexpensive starting material pyrrole using sequential flow operations. The optimized flow conditions allowed for the production of 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine in a significantly shorter time compared to traditional batch procedures, with a high yield and enhanced safety.
Article
Biochemical Research Methods
Juliane Diehm, Lennart Witting, Frank Kirschhoefer, Gerald Brenner-Weiss, Matthias Franzreb
Summary: Continuous manufacturing is increasingly important in the (bio-)pharmaceutical industry, and there is a need for powerful continuous analytical tools. This study demonstrates the feasibility of using a micro simulated moving bed chromatography system for continuous on-line sample preparation for mass spectrometry. The integration of this system significantly increases mass spectrometry sensitivity and provides a versatile tool for quality assessment in biopharmaceutical processes.
ANALYTICAL AND BIOANALYTICAL CHEMISTRY
(2023)
Article
Chemistry, Applied
Cuixian Yang, Hanzhou Feng, Kevin Stone
Summary: In this study, a cost-efficient approach utilizing data-rich experimentation was developed to characterize propionyl phosphate hydrolysis reaction kinetics. A quantitative FTIR multivariant model was established using FTIR-based PAT and offline NMR calibration, integrated with RTS to generate a massive database in a single experiment. This integrative platform can be broadly applied to investigations of the kinetics of various liquid-phase reactions.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2021)
Article
Chemistry, Physical
Lihua Du, Lingyan Zheng, Yue Pan, Zhikai Sheng, Shiyi Zhang, Hang Lin, Aoying Zhang, Hanjia Xie, Xiping Luo
Summary: A highly efficient method for the synthesis of cinnamamides catalyzed by Lipozyme (R) TL IM in continuous-flow microreactors was developed. The method offers short residence time, mild reaction conditions, easy control of the reaction process, and the possibility of catalyst recycling.
Article
Chemistry, Multidisciplinary
Daniel Jansen, Dominique Ectors, Xiangming Kong, Christian Schmidtke, Florian Deschner, Joachim Pakusch, Ekkehard Jahns, Juergen Neubauer
Summary: This study simultaneously monitored the formation of latex film and phase development in cementitious systems using H-1-time-domain-NMR for the first time. The obtained results were validated using classical analytical methods.
Editorial Material
Chemistry, Physical
Benjamin P. MacLeod, Fraser G. L. Parlane, Amanda K. Brown, Jason E. Hein, Curtis P. Berlinguette
Summary: Flexible automation technology can accelerate the research and development process, reducing costs and saving time; helping researchers apply new science and technology faster than ever before.
Article
Multidisciplinary Sciences
Madeleine C. Deem, Joshua S. Derasp, Thomas C. Malig, Kea Legard, Curtis P. Berlinguette, Jason E. Hein
Summary: Ring walking in Buchwald-Hartwig amination reactions is influenced by the chelating nature of the ligand, while the resting state of the catalyst has no impact. The study also differentiates catalysts that undergo ring walking from diffusion-controlled coupling. The insights gained from this study were used to achieve the desymmetrization of a tetrabrominated precursor.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Physical
Antonio J. LaPorte, Yao Shi, Jason E. Hein, Martin D. Burke
Summary: Stereospecific Csp(3) Suzuki-Miyaura cross-coupling simplifies the synthesis of stereochemically complex small molecules, but current methods are not compatible with complex building blocks commonly found in natural products and other complex targets. This study presents a method for embedding the alpha-methyl-beta-hydroxyl motif within stereochemically defined secondary alkyl boronic ester building blocks, allowing for stereospecific cross-coupling. The use of beta-aryloxysilyl groups addresses the decrease in reactivity and side reactions associated with beta-oxygen-containing Csp(3) boronic esters. Mechanistic studies reveal the activation of a dihydroxysiloxaborolate as a transmetalation partner in a stereospecific process that retains configuration.
Article
Chemistry, Organic
Madeleine C. Deem, Jason E. Hein
Summary: Online HPLC reaction progress monitoring provides detailed data-rich profiles, but it is difficult to determine kinetic concentrations from peak areas. By utilizing a system of linear equations, it is possible to estimate the absolute response factors of all species if the reaction's overall mass balance is known and some analytical trend for all relevant species can be recorded. We propose a method using the Microsoft Solver plug-in to convert time course profiles to reagent concentrations without analytical standards.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Physical
Madeleine C. Deem, Isabelle Cai, Joshua S. Derasp, Paloma L. Prieto, Yusuke Sato, Junliang Liu, Andrew J. Kukor, Jason E. Hein
Summary: Kinetic investigations are crucial for optimizing reaction parameters and development through providing important mechanistic information. Modern kinetic analysis methods, such as RPKA and VTNA, offer numerous advantages over traditional initial rate methods, especially when combined with reaction monitoring technologies. However, misinterpretation of data may occur due to a lack of careful observation and optimization. In this Perspective, we emphasize some commonly overlooked considerations in kinetic studies, based on our experiences, and present a general guide for properly optimizing reactions and analytics prior to obtaining kinetic data.
Article
Chemistry, Physical
Yusuke Sato, Junliang Liu, Ikenna Edward Ndukwe, Maria Victoria Silva Elipe, Daniel J. Griffin, James I. Murray, Jason E. Hein
Summary: Monitoring the reaction progress of biphasic reaction mixtures has been a challenge due to the lack of in-line separation and analysis of each phase. This study presents a novel sampling technology using online HPLC and multinuclear flow NMR spectroscopy to accurately monitor the reaction progress in biphasic mixtures. A biphasic sampling platform was developed to circulate a single phase of the mixture for analysis, and its utility was demonstrated in analyzing boronic acid distribution under basic conditions and monitoring the progress of a biphasic Suzuki-Miyaura cross-coupling reaction.
Article
Chemistry, Multidisciplinary
Andrew J. Kukor, Frederic St-Jean, Andreas Stumpf, Thomas C. Malig, Katarzyna A. Piechowicz, Kenji Kurita, Jason E. Hein
Summary: The recently reported crystallization-induced diastereomer transformation (CIDT) of a precursor to navoximod was investigated using online HPLC via a modified EasySampler probe. The probe enables selective solution phase sampling of heterogeneous reaction mixtures. Both chiral and achiral stationary phases were used to study the effects of time, temperature, and equivalents of chiral resolving agent on reaction yield and e.e. An inline racemization approach was applied after the CIDT and selective racemization over decomposition was demonstrated.
REACTION CHEMISTRY & ENGINEERING
(2023)
Article
Chemistry, Multidisciplinary
Tristan Maschmeyer, Breanna Conklin, Thomas C. Malig, David J. Russell, Kenji L. Kurita, Jason E. Hein, Jose G. Napolitano
Summary: Nuclear magnetic resonance (NMR) spectroscopy is a powerful analytical technique that provides quantitative and structural information about multiple components in a sample. This study describes a simple and robust method to determine concentration conversion factors using linear regression models in NMR systems, and applies this method to monitor a pharmaceutically relevant amide coupling reaction.
MAGNETIC RESONANCE IN CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Junliang Liu, Yusuke Sato, Viveka K. Kulkarni, Angus I. Sullivan, Wenyu Zhang, Cathleen M. Crudden, Jason E. Hein
Summary: Atomically precise gold nanoclusters (AuNCs) are interesting nanomaterials with potential applications in catalysis, bioimaging, and optoelectronics. However, the synthetic methods for AuNCs lack in situ and real-time reaction monitoring, limiting the understanding of their formation mechanisms and hindering optimization. In this study, the utility of HPLC-MS as a monitoring methodology in the synthesis of two NHC-protected gold nanoclusters was demonstrated, providing new insights into the reaction dynamics and rapid optimization.
Article
Chemistry, Multidisciplinary
Andrew J. Kukor, Noah Depner, Isabelle Cai, John L. Tucker, Jeffrey C. Culhane, Jason E. Hein
Summary: This article presents a multi-well continuous CIDT approach with inline racemization of the solution phase. By using in-house built PATs and a flow reactor, enantiopure salt of TBZ was successfully crystallized and multigram quantities of enantiopure material were harvested through inline racemization and careful control of crystallization conditions. The use of PATs to observe and quantify the composition of both the solid and solution phases made this control possible.
Article
Chemistry, Multidisciplinary
Junliang Liu, Yusuke Sato, Fan Yang, Andrew J. Kukor, Jason E. Hein
Summary: Researchers have developed an adaptive auto-synthesizer that uses online HPLC and FTIR measurements to adapt to the changing reactivities of different substrates, allowing precise control of reaction conditions.
Article
Chemistry, Multidisciplinary
Tristan Maschmeyer, Lars P. E. Yunker, Jason E. Hein
Summary: This article presents a stopped-flow benchtop NMR system that allows for convenient acquisition of quantitative reaction monitoring data and has been successfully applied to monitor difficult-to-detect model reaction systems.
REACTION CHEMISTRY & ENGINEERING
(2022)
