Date: 21 November 2025 | Category: News
Authors: Margherita Bazzoni, Yuliia Horbenko, Nour El Sabbagh, Achille Marchand, Magdalena Grochowska-Tatarczak, Aurélie Bernard, Patrick Giraudeau, François-Xavier Felpin, and Jean-Nicolas Dumez.
Bazzoni, Dumez and co-workers from Nantes Université have provided a valuable overview of the development of ‘in flow’ high-field NMR spectroscopy as a means for real-time reaction monitoring. Ultrafast 2D NMR correlation spectroscopy (UF COSY) and fast diffusion ordered NMR spectroscopy (DOSY) using one-shot double-stimulated echo (DSTE) pulse sequences are both discussed, with examples of the utility of both provided.[1]
Figure 1: Integration of in-line NMR for reaction monitoring in real-time The importance of real-time reaction monitoring
Monitoring reaction progress during synthesis is extremely important, providing valuable information relating to the identification and quantification of starting materials, products and by-products. While there are many monitoring methods available, including TLC, mass spectrometry and in-line infra-red spectroscopy, the use of NMR is often considered the ‘gold standard’ due to the detailed structural and relative information that can be derived from reaction mixtures, coupled with minimal sample preparation and the non-destructive mode of data collection. However, the use of NMR to monitor reactions is non-trivial. In some cases, removal of aliquots of reaction mixture can give insight or in others the reaction can be undertaken in an NMR tube in the spectrometer itself,[2] but these approaches come with severe limitations that hinder general applicability, especially when the synthesis is optimised to use flow chemistry.
The value of in-line NMR reaction monitoring
Flow NMR, where the sample of interest is directly passed through an NMR spectrometer, is rapidly gaining interest for monitoring applications, and offers several advantages:
- Real-time monitoring
- Reactions can be run under standard conditions in either batch or flow mode
- Further reagents or solvents can be added while the reaction is underway
- Continuous stirring is facilitated
- Manual operations are minimized, reducing the impact of analysis on the reaction mixture
- Photochemical- or microwave-mediated reactions can be monitored.
Benchtop NMR spectrometers are a regular feature, although these are limited by the low field-strength of approximately 2 Tesla, which limits the resolution and sensitivity of the instrument. However, recent advances mean that flow NMR using high-field spectrometers is now possible, with the development of flow cells that can be inserted into classical 5 mm NMR probes [1, 3, 4, 5]. Fast multidimensional NMR experiments are particularly useful to address the complexity of reaction mixtures,[6] for which 1D 1H spectra are often complicated by significant signal overlap, especially when the molecular structures of reagents and products are similar.
UF-COSY and one-shot DSTE: Complementary techniques for flow-based reaction monitoring
The review article, by Bazzoni, Dumez and co-workers, outlines the current state of monitoring reactions using flow NMR on high-field instruments. Online monitoring of batch and in-line monitoring of flow reactions are outlined, as well as approaches for data collection, ‘good practice’ and the types of NMR experiment that are possible. The Vapourtec peristaltic SF-10 pump was highlighted as being of particular utility as:
- The sample is only in contact with the pump tube, a consumable
- This pump has proven suitable for pumping gases and solid matter
- The pump is compatible with three types of tubing which provide different chemical compatibilities, alongside support for a range of flow rates and pressures.
Key examples using a fully integrated 500 MHz spectrometer are given, including using in-line UF COSY for analysis of a batch-mode organocatalyzed condensation of citral and 1,3-cyclohexanedione, which provided kinetic data, and a flow-based photochemical thiol-ene reaction. In-line DOSY was demonstrated for a batch reaction di-imination of diphenylamine in non-deuterated acetonitrile.
References:
[1] Fast Multidimensional Flow Nuclear Magnetic Resonance at High Field for Real-Time Reaction Monitoring and Flow Synthesis (M. Bazzoni, Y. Horbenko, N. El Sabbagh, A. Marchand, M. Grochowska-Tatarczak, A. Bernard, P. Giraudeau, F.-X. Felpin, and J.-N. Dumez, Chem. Eur., 2025, 5, e2024400061). https://doi.org/10.1002/cmtd.202400061
[2] Mechanistic analysis by NMR spectroscopy: A users guide (Y. Ben-Tal, P. J. Boaler, H. J. A. Dale, R. E. Dooley, N. A. Fohn, Y. Gao, A. García-Domínguez, K. M. Grant, A. M. R. Hall, H. L. D. Hayes, M. M. Kucharski, R. Wei, G. C. Lloyd-Jones, Prog. Nucl. Mag. Reson. Spectrosc., 2022, 129, 28–106). https://doi.org/10.1016/j.pnmrs.2022.01.001
[3] Practical aspects of real-time reaction monitoring using multi-nuclear high resolution FlowNMR spectroscopy (A. M. R. Hall, J. C. Chouler, A. Codina, P. T. Gierth, J. P. Lowe, U. Hintermair, Catal. Sci. Technol., 2016, 6, 8406–8417). https://doi.org/10.1039/C6CY01754A
[4] NMR flow tube for online NMR reaction monitoring (D. A. Foley, E. Bez, A. Codina, K. L. Colson, M. Fey, R. Krull, D. Piroli, M. T. Zell, B. L. Marquez, Anal. Chem., 2014, 86, 12008–12013). https://doi.org/10.1021/ac502300q
[5] A simple flowcell for reaction monitoring by NMR (M. Khajeh, M. A. Bernstein, G. A. Morris, Magn. Reson. Chem., 2010, 48, 516). https://doi.org/10.1002/mrc.2610