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Fast Multidimensional Flow Nuclear Magnetic Resonance at High Field for Real-Time Reaction Monitoring and Flow Synthesis
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High-field flow NMR enables real-time monitoring of chemical reactions, but 1D ¹H spectra are often limited by overlap and ambiguity. Fast 2D methods like ultrafast 2D NMR and diffusion-ordered spectroscopy provide rapid correlation data compatible with flowing samples, making them powerful tools for online reaction monitoring and flow synthesis.
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Margherita Bazzoni, Yuliia Horbenko, Nour El Sabbagh, Achille Marchand, Magdalena Grochowska-Tatarczak, Aurélie Bernard, Patrick Giraudeau, François-Xavier Felpin and Jean-Nicolas Dumez
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Chemistry Methods
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05/2025
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Clean H NMR Spectra of Products Directly from Batch and Flow Reaction Mixtures
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NMR spectroscopy is widely used for reaction monitoring, but peak overlap often limits analysis. Combining fast diffusion NMR with multiway analysis enables extraction of clean spectra and concentration profiles, even in continuous flow, providing robust high-quality data for tracking chemical reactions.
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Yuliia Horbenko, Martin Jaudronnet, Nour El Sabbagh, Margherita Bazzoni, Aurélie Bernard, Mathias Nilsson, Patrick Giraudeau, François-Xavier Felpin and Jean-Nicolas Dumez
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ChemistryEurope
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04/2025
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Pure Shift NMR in Continuous Flow
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Flow NMR enables in-line analysis, process optimization, and real-time reaction monitoring, but complex 1D ¹H spectra can be challenging to interpret. Pure shift NMR simplifies ¹H spectra, and with an adapted acquisition scheme, solvent suppression, and velocity compensation, it can now be applied to continuously flowing samples. This approach provides ultrahigh-resolution data, enhancing the capabilities of flow NMR for reaction monitoring and other applications.
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Margherita Bazzoni, Armand Régheasse, Elsa Caytan, François-Xavier Felpin, Patrick Giraudeau, Aurélie Bernard, Ralph W. Adams, Gareth A. Morris, Mathias Nilsson and Jean-Nicolas Dumez
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Chemistry-A European Journal
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10/2024
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Catalyst Speciation and Deactivation in the Ruthenium mediated transformation of Ethynyl-β-Ionol to α,β-Unsaturated Esters for Vitamin A Synthesis
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The anti-Markovnikov addition of carboxylic acids to propargylic alcohols produces valuable unsaturated esters, but low catalyst turnover (<100) limits industrial use. Multi-nuclear high-resolution FlowNMR revealed key carboxylate complexes, catalyst deactivation kinetics, and the impact of acid type on stability. Optimizing reaction conditions significantly increased catalyst productivity, achieving TONs >450 for ethynyl-β-ionol and >2000 for phenylacetylene.
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Asad Saib,Roman Goy, Jonathan Medlock, Bettina Wüstenberg, Gabriele Kociok-Köhn, Catherine L. Lyall, John P. Lowe and Ulrich Hintermair
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Catalysis Science & Technology
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10/2024
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Autonomous reaction self-optimization using in-line high-field NMR spectroscopy
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Autonomous self-optimizing flow reactors combine automated flow systems with feedback algorithms and in-line high-field NMR to efficiently optimize chemical reactions. Using 1D ¹H NMR with solvent suppression, quantitative measurements guide the Nelder–Mead algorithm to optimize yield or throughput by adjusting residence time, stoichiometry, and catalyst loading. This integration enhances precision and efficiency in complex reaction optimization, advancing chemical synthesis capabilities.
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Nour El Sabbagh,Margherita Bazzoni,Yuliia Horbenko, Aurélie Bernard, Daniel Cortés-Borda, Patrick Giraudeau, François-Xavier Felpin and Jean-Nicolas Dumez
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Reaction Chemistry & Engineering
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06/2024
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In-Situ Investigations of Polyoxometalate-Catalysed Biomass Oxidation to Formic Acid by Using Multinuclear High Resolution Flow NMR Spectroscopy
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Biomass valorization using polyoxometalate (POM) catalysts offers a sustainable route for chemical production, but understanding additive effects is crucial for optimization. Using FlowNMR, the oxidation of glycolaldehyde with H5PV2Mo10O40 (HPA-2) was studied in situ, identifying the active catalyst isomer and revealing how additives influence reaction kinetics. These insights provide a foundation for improving POM-catalyzed aerobic oxidation of biomass.
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Jan-Dominik H. Krueger, Maximilian J. Poller, Catherine Lyall, John Lowe, Ulrich Hintermair and Jakob Albert
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ChemCatChem
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04/2024
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Water co-catalysis in aerobic olefin epoxidation mediated by ruthenium oxo complexes
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A versatile Ru-porphyrin catalyst enables aerobic epoxidation of aromatic and aliphatic alkenes under mild conditions, achieving up to 95% yield and TONs of 300. FlowNMR studies show that water activates the RuVI di-oxo complex, stabilizes the RuIV mono-oxo intermediate, and aids catalyst regeneration, while also revealing water-dependent kinetics and side reactions responsible for catalyst deactivation.
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Qun Cao, Martin Diefenbach, Calum Maguire, Vera Krewald, Mark J. Muldoon and Ulrich Hintermair
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Chemical Science
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01/2024
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Charge-Dependent Crossover in Aqueous Organic Redox Flow Batteries Revealed Using Online NMR Spectroscopy
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Aqueous organic redox-flow batteries (AORFBs) face capacity decay due to crossover of redox-active materials. Using online ¹H FlowNMR with a decoupled pump, crossover can be quantitatively monitored in real time under operating conditions. In a 2,6-DHAQ/ferrocyanide model, charging doubled 2,6-DHAQ crossover, highlighting migration effects. This method provides deeper insight into membrane performance and aids development of improved AORFBs.
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Emma J. Latchem,Thomas Kress,Peter A. A. Klusener, R. Vasant Kumar and Alexander C. Forse
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The Journal of Physical Chemistry Letter
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01/2024
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Broadband ultrafast 2D NMR spectroscopy for online monitoring in continuous flow
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Flow NMR enables real-time reaction monitoring under realistic conditions. Ultrafast (UF) 2D NMR schemes allow acquisition of broadband homonuclear 2D spectra in under 90 seconds for continuously flowing samples. Using transverse spatial encoding, interleaved acquisition, and optimized solvent suppression, high scan-to-scan stability is achieved, enabling high-time-resolution monitoring, demonstrated on an organocatalyzed condensation reaction.
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Célia Lhoste, Margherita Bazzoni, Justine Bonnet, Aurélie Bernard, François-Xavier Felpin, Patrick Giraudeau and Jean-Nicolas Dumez
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Analyst
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08/2023
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Chapter 9: Fast 2D NMR for Reaction and Process Monitoring
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Real-time NMR monitoring provides quantitative and structural insights into chemical reactions, even on sub-second timescales. Fast 2D NMR methods, including ultrafast 2D NMR and non-uniform sampling, overcome the time limitations of conventional 2D experiments, enabling analysis of overlapping or transient species. Various setups, such as benchtop spectrometers, flow-NMR, and fast-mixing apparatus, expand monitoring capabilities. Applications in synthesis and catalysis demonstrate the potential of fast 2D NMR for detailed reaction analysis.
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M. Bazzoni, B. Lorandel, C. Lhoste; P. Giraudeau and Jean-Nicolas Dumez
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Royal Society of Chemistry
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05/2023
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Paramagnetic Relaxation Agents for Enhancing Temporal Resolution and Sensitivity in Multinuclear FlowNMR Spectroscopy
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FlowNMR sensitivity for low-sensitivity nuclei like ³¹P and ¹³C is limited by short residence times. Paramagnetic relaxation agents (PRAs), especially [Cr(tmhd)₃], reduce T₁ times without line broadening or chemical interference. This enhances ¹H, ³¹P, and ¹³C FlowNMR signals, enabling quantitative monitoring of catalytic reactions such as Rh-catalyzed hydroformylation.
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Alejandro Bara-Estaún, Marie C. Harder, Catherine L. Lyall, John P. Lowe, Elizaveta Suturina and Ulrich Hintermair
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Chemistry -A European Journal
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03/2023
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Understanding Rh‐catalysed Hydroformylation with Phosphite Ligands through Catalyst Speciation Analysis by Operando FlowNMR Spectroscopy
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The effect of phosphite ligands (triphenylphosphite, Alkanox, BiPhePhos) on Rh-catalyzed hydroformylation was studied using multi-nuclear operando FlowNMR. Quantitative catalyst distribution maps reveal that phosphites enhance activity by reducing inactive Rh⁰ dimer formation during pre-activation and at reaction end. [(Alkanox)Rh(acac)] complexes also show high stability, enabling easy post-catalytic Rh recovery with 2,4-pentanedione.
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Alejandro Bara-Estaún, Catherine L. Lyall, John P. Lowe, Paul G. Pringle, Paul C. J. Kamer, Robert Franke and Ulrich Hintermair
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ChemCatChem
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02/2023
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In-line Multidimensional NMR Monitoring of Photochemical Flow Reactions
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This work demonstrates in-line monitoring of a flow photochemical reaction using 1D and ultrafast 2D NMR at high field. While 1D ¹H spectra suffice for simple substrates, ultrafast 2D COSY experiments (≤70 s) resolve overlaps in complex molecules and provide reliable quantitative data. This approach enables efficient reaction monitoring and rapid screening of reaction conditions.
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Margherita Bazzoni, Célia Lhoste, Justine Bonnet, Kouakou Eric Konan, Aurélie Bernard, Patrick Giraudeau, François-Xavier Felpin and Jean-Nicolas Dumez
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Chemistry-A European Journal
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01/2023
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Theoretical analysis of flow effects in spatially encoded diffusion NMR
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Spatially encoded diffusion NMR (SPEN DNMR) enables time-efficient measurement of translational diffusion, useful in organic, polymer, and supramolecular chemistry. Flow or convective motion can distort SPEN DNMR data, limiting accuracy in applications like online reaction monitoring. This work provides a detailed theoretical analysis of flow effects and their compensation, validated by Fokker–Planck simulations, and examines constant, laminar, and convective flows, guiding the design of fast, accurate diffusion NMR experiments.
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Rituraj Mishra and Jean-Nicolas Dumez
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The Journal of Chemical Physics
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01/2023
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Online Reaction Monitoring with Fast and Flow-Compatible Diffusion NMR Spectroscopy
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Flow NMR enables mechanistic insights and reaction optimization, but classic DOSY methods are challenging under flow conditions. A fast, flow-compatible diffusion NMR experiment is presented, allowing accurate diffusion measurements at up to 3 mL/min. Applied to Schiff base synthesis, it achieves ~2 min time resolution, opening new opportunities for reaction monitoring in continuous flow.
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Achille Marchand, Rituraj Mishra, Aurélie Bernard and Jean-Nicolas Dumez
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Chemistry-A European Journal
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09/2022
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Mapping catalyst activation, turnover speciation and deactivation in Rh/PPh3-catalysed olefin hydroformylation
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Multi-nuclear operando FlowNMR provides new insights into Rh/PPh₃-catalyzed hydroformylation of 1-hexene. Selectively excited ¹H and ³¹P{¹H} experiments quantify key hydrido- and acyl-rhodium intermediates, as well as dormant dimeric carbonyls, explaining catalyst stability and activity. CO-lean conditions enhance catalysis by suppressing dimer formation, while precursor activation and [RhH(CO)(PPh₃)₃] thermal stability are evaluated. Controlled temperature gradients improve quantitative monitoring of dynamic catalyst systems.
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Alejandro Bara-Estaún, Catherine L. Lyall, John P. Lowe, Paul G. Pringle,Paul C. J. Kamer, Robert Franke and Ulrich Hintermair
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Catalysis Science & Technology
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07/2022
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Convenient and accurate insight into solution-phase equilibria from FlowNMR titrations
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Multi-nuclear high-resolution FlowNMR enables online analysis of complex solution-phase equilibria, combining the convenience of in situ measurements with the specificity of high-resolution NMR. Automated titrations in a closed-loop flow setup allow integration of sensors like pH probes and UV-vis cells, and glovebox compatibility permits study of air- and moisture-sensitive systems. This approach is demonstrated for Brønsted and Lewis acid/base titrations, hydrogen bonding, and dynamic metal–ligand interactions.
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Daniel B. G. Berry, Ian Clegg, Anna Codina, Catherine L. Lyall, John P. Lowe and Ulrich Hintermair
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Reaction Chemistry & Engineering
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06/2022
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Fast and accurate diffusion NMR acquisition in continuous flow
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FlowNMR has emerged as a powerful tool for online reaction monitoring. This work extends its capabilities with FlowDOSY, using convection compensation and low-pulsation pumps or flow-effect corrections to obtain accurate diffusion coefficients at flow rates up to 4 mL/min in under 5 minutes.
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Isabel A. Thomlinson, Matthew G. Davidson, Catherine L. Lyall, John P. Lowe and Ulrich Hintermair
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Chemical Communications
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06/2022
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Ultrafast 2D NMR for the analysis of complex mixtures
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Ultrafast (single-scan) 2D NMR is a versatile tool for analyzing complex mixtures where acquisition time is critical, such as ongoing reactions, moving samples, or high-throughput studies. This review summarizes key concepts, features, limitations, and methodological advances that enhance its analytical power. Major applications include reaction and process monitoring, metabolomics, analysis of hyperpolarized mixtures, and studies in oriented media, focusing on high-resolution liquid-state 2D experiments with at least one spectroscopic dimension.
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Célia Lhoste, Benjamin Lorandel, Clément Praud, Achille Marchand, Rituraj Mishra, Arnab Dey, Aurélie Bernard, jean-Nicolas Dumez and Patrick Giraudeau
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Progress in Nuclear Magnetic Resonance Spectroscopy
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05/2022
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Mechanistic analysis by NMR spectroscopy: A users guide
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This tutorial-style review showcases solution-phase NMR for studying mechanisms in organic and organometallic reactions. It covers techniques, instrumentation, and data analysis, including DOSY, isotopic methods, and kinetics. Fifteen case studies highlight advanced approaches such as in situ, flow, stopped-flow, pure shift, and dynamic nuclear polarization NMR, demonstrating its versatility in mechanistic studies
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Yael Ben-Tal, Patrick J. Boaler, Harvey J.A. Dale, Ruth E. Dooley, Nicole A. Fohn, Yuan Gao, Andrés García-Domínguez, Katie M. Grant, Andrew M.R. Hall, Hannah L.D. Hayes, Maciej M. Kucharski, Ran Wei and Guy C. Lloyd-Jones
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Progress in Nuclear Magnetic Resonance Spectroscopy
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04/2022
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Does the Configuration at the Metal Matter in Noyori–Ikariya Type Asymmetric Transfer Hydrogenation Catalysts?
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Operando FlowNMR and NOE spectroscopy reveal two diastereomeric hydride complexes in Noyori–Ikariya [(arene)RuCl(TsDPEN)] catalysis. The λ-(R,R)SRu isomer is favored and dominates asymmetric ketone reduction, while the minor λ-(R,R)RRu is less active, supporting a lock-and-key mechanism for enantioselective transfer hydrogenation.
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Andrew M. R. Hall, Daniel B. G. Berry, Jaime N. Crossley, Anna Codina, Ian Clegg, John P. Lowe, Antoine Buchard and Ulrich Hintermair
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ACS catalysis
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10/2021
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Engineering aspects of FlowNMR spectroscopy setups for online analysis of solution-phase processes
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FlowNMR enables real-time monitoring of solution-phase chemistry, providing insights into dynamic behavior in complex systems. The design of flow cells and setups—material, dimensions, and components—significantly affects data quality. This review addresses key engineering considerations to avoid common pitfalls and supports the development of good practice guidelines (GxP) for FlowNMR in academic and industrial applications
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Asad Saib, Alejandro Bara-Estaún, Owen J. Harper, Daniel B. G. Berry, Isabel A. Thomlinson, Rachael Broomfield-Tagg, John P. Lowe, Catherine L. Lyall and Ulrich Hintermair
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Reaction Chemistry & Engineering
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08/2021
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Multi-Nuclear, High-pressure, Operando FlowNMR Spectroscopic Study of Rh/PPh3 - Catalysed Hydroformylation of 1-Hexene
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Real-time multinuclear FlowNMR studied 1-hexene hydroformylation with [Rh(acac)(CO)₂]/PPh₃ at 50 °C, providing quantitative reaction curves, rates, and selectivities under true operando conditions. Interleaved ³¹P{¹H}, selective ¹H, and stopped-flow experiments identified Rh–phosphine intermediates, showing [RhH(CO)(PPh₃)₃] rapidly forms bis-phosphine isomers entering the catalytic cycle, and revealing a new mono-phosphine acyl complex as an in-cycle intermediate.
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Alejandro Bara-Estaún, Catherine L. Lyall, John P. Lowe, Paul G. Pringle, Paul C. J. Kamer, Robert Frank and Ulrich Hintermair
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Faraday Discussions
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03/2020
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Online reaction monitoring by single-scan 2D NMR under flow conditions
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Flow NMR combined with ultrafast 2D NMR (UF2DNMR) enables real-time monitoring of circulating solution mixtures, providing kinetic and mechanistic insights. UF2DNMR collects 2D data in under one second but is sensitive to sample motion; pulse-sequence and hardware adjustments overcome flow-related interference. The approach is demonstrated with a saponification reaction, highlighting its potential for online reaction monitoring.
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Corentin Jacquemmoz, François Giraud and Jean-Nicolas Dumez
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Analyst
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11/2019
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Insight into catalyst speciation and hydrogen co-evolution during enantioselective formic acid-driven transfer hydrogenation with bifunctional ruthenium complexes from multi-technique operando reaction monitoring
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Transfer hydrogenation of acetophenone with [(mesitylene)RuCl(R,R)-(TsDPEN)] was studied using FlowNMR, FlowUV-Vis, head-space MS, and chiral HPLC in an automated recirculating setup. Results reveal a switch from formic acid dehydrogenation to hydrogen transfer via a Ru-hydride, with a Ru-formate species as the key intermediate. Hydrogen bonding in the formic acid/triethylamine mixture serves as a sensitive ¹H NMR probe for reaction activity and optimization.
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Daniel B. G. Berry, Anna Codina, Ian Clegg, Catherine L. Lyall, John P. Lowe and Ulrich Hintermair
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Faraday Discussions
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06/2019
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Kinetics of Asymmetric Transfer Hydrogenation, Catalyst Deactivation, and Inhibition with Noyori Complexes As Revealed by Real-Time High-Resolution FlowNMR Spectroscopy
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Operando ¹H FlowNMR of [(arene)(TsDPEN)RuCl]-catalyzed hydrogen transfer from isopropyl alcohol to aryl ketones tracked the key [(mesitylene)(TsDPEN)RuH] intermediate. Polarization transfer experiments showed substrate interactions, while kinetic analysis revealed two deactivation pathways: base-induced competitive inhibition and first-order hydride decay. Isotopic labeling identified arene loss as the entry point to Ru nanoparticle formation via hydride-bridged intermediates.
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Andrew M. R. Hall, Peilong Dong, Anna Codina, John P. Lowe and Ulrich Hintermair
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ACS Catalysis
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01/2019
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Photo-biocatalytic One-Pot Cascades for the Enantioselective Synthesis of 1,3-Mercaptoalkanol Volatile Sulfur Compounds
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A one-pot photo-biocatalytic cascade synthesizes enantiomerically pure 1,3-mercaptoalkanols. Two new KRED biocatalysts with opposite enantioselectivity efficiently convert a broad range of substrates. The cascade, combining photocatalytic thio-Michael addition and biocatalytic ketoreduction in water, provides a green, high-yielding, and highly enantioselective route to these volatile sulfur compounds.
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Kate Lauder, Anita Toscani, Yuyin Qi, Jesmine Lim, Simon J. Charnock, Krupa Korah and Daniele Castagnolo
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Angewandte Chemie International Edition
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03/2018
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Online monitoring of a photocatalytic reaction by real-time high resolution FlowNMR spectroscopy
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FlowNMR enables mechanistic studies of photochemical reactions under realistic light and air conditions. Eosin Y–mediated photo-oxidation of N-allylbenzylamine produces imines as primary products, with aldehydes forming over time. Adjustable flow conditions allow in-line probe experiments to reveal the photocatalyst’s mode of action.
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Andrew M. R. Hall,Rachael Broomfield-Tagg, Matthew Camilleri, David R. Carbery, Anna Codina, David T. E. Whittaker, Steven Coombes, John P. Lowe and Ulrich Hintermair
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Chemical Communications
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11/2017
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NMR reaction monitoring in flow synthesis
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Recent advances in flow chemistry coupled with in-line and on-line NMR analysis are reviewed, covering macro- and microreactors, standard and microcoil NMR probes, and high-resolution and benchtop instruments. Applications include synthetic studies, kinetic and thermodynamic measurements, and reaction optimization on μL scales, often in single experiments. Automated software for reaction monitoring and optimization is also discussed.
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M. Victoria Gomez and Antonio de la Hoz
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Journal of Organic Chemistry
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02/2017
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Practical aspects of real-time reaction monitoring using multi-nuclear high resolution FlowNMR spectroscopy
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FlowNMR is a powerful, non-invasive technique for real-time reaction monitoring under realistic conditions. With recent commercial high-resolution solutions, its use is growing in academia and industry. Practical considerations—including apparatus design, flow effects, acquisition parameters, and data processing—are critical for accurate kinetic measurements. Flow-induced NMR signal variations can be corrected and even leveraged to enhance temporal resolution.
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Andrew M. R. Hall, Jonathan C. Chouler, Anna Codina, Peter T. Gierth, John P. Lowe and Ulrich Hintermair
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Catalysis Science & Technology
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09/2016
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Coupling and optimisation of online nuclear magnetic resonance spectroscopy and mass spectrometry for process monitoring to cover the broad range of process concentration
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Real-time monitoring of chemical reactions was achieved by combining 500 MHz ¹H NMR with a compact mass spectrometer in a flow setup. NMR provided accurate quantitation of major components, while MS detected low-level species. Optimized sample transfer extended MS linearity to 10% of maximum concentration. This integrated approach enables comprehensive qualitative and quantitative analysis across the full reaction range and was demonstrated on a batch reaction.
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Alexander Blanazs, Tony W. T. Bristow, Steven R. Coombes, Tom Corry, Mike Nunn and Andrew D. Ray
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Magnetic Resonance in Chemistry
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07/2016
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A detailed mechanistic investigation into the reaction of 3-methylpentanoic acid with Meldrum's acid utilizing online NMR spectroscopy
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Online NMR spectroscopy was used to investigate the reaction of 3-methylpentanoic acid with Meldrum’s acid, expanding studies on the synthesis of the API imagabalin. The analysis confirms the previously hypothesized dimer anhydride intermediate, 3-methylpentanoic anhydride, and reveals for the first time the presence of 3-methylpentanoyl chloride as an acyl chloride intermediate, providing new mechanistic insights.
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Anna L. Dunn, Anna Codina, David A. Foley, Brian L. Marquez and Mark T. Zell
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Magnetic Resonance in Chemistry
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08/2015
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Reaction monitoring using online vs tube NMR spectroscopy: seriously different results
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This study compares NMR reaction monitoring methods—online NMR, static tubes, and periodic tube inversion—and their impact on observed reaction kinetics. Analysis of three reactions shows that measured rates vary significantly with the monitoring approach, highlighting the importance of method choice when interpreting kinetic data from NMR experiments.
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David A. Foley, Anna L. Dunn and Mark T. Zell
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Magnetic Resonance in Chemistry
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08/2015
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NMR Flow Tube for Online NMR Reaction Monitoring
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A 5 mm NMR flow tube compatible with standard 5 mm probes was developed, allowing reaction monitoring and kinetic studies of flowing mixtures without a specialized flow probe. This versatile setup works across different spectrometers and field strengths. Its applicability is demonstrated by monitoring the formation of a diimine from p-phenylenediamine and isobutyraldehyde.
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David A. Foley, Eckhard Bez, Anna Codina, Kimberly L. Colson, Michael Fey, Robert Krul, Don Piroli, Mark T. Zell and Brian L. Marquez
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Analytical Chemistry
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11/2014
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