NMR Flow Tube for Online NMR Reaction Monitoring

Abstract

In this paper we describe the development of a 5 mm NMR flow tube that can be used in a standard 5 mm NMR probe, enabling the user to conduct experiments on flowing samples or, more specifically, on flowing reaction mixtures. This enables reaction monitoring or kinetic experiments to be conducted by flowing reaction mixtures from a reaction vessel to detection in the coil area of the NMR, without the need for a specialized flow NMR probe. One of the key benefits of this flow tube is that it provides flexibility to be used across a range of available spectrometers of varying magnetic field strengths with a standard 5 mm probe setup. The applicability of this flow tube to reaction monitoring is demonstrated using the reaction of p-phenylenediamine and isobutyraldehyde to form the diimine product.

Reaction monitoring using online vs tube NMR spectroscopy: seriously different results

“…This study was undertaken to evaluate how basic NMR tube monitoring techniques compare with following the progress of a reaction using an online NMR system such as the one developed in our laboratory . While numerous reports of kinetic and mechanistic studies using both standard NMR tube and online approaches have appeared in the literature, none have undertaken a systematic comparison of NMR reaction monitoring techniques.…”

“…There are some limitations associated with monitoring a reaction online because of the distance between the reaction vessel and the detection cell, which can influence sample transfer time and temperature gradients. Details of the online NMR spectroscopy system used in this study have been published previously, and a number of reports of the characteristics of online NMR systems have provided in‐depth analysis of the considerations when conducting this type of analysis [5,6b,17] . Online NMR also allows for the introduction of other analytical instruments in‐line, but requires specialized equipment that may not be available to all users.…”

“…Temperature control was achieved by setting reaction vessel, sample loop, and spectrometer to the specified temperature. The flow rate was set to 4 ml/min . Spectra were acquired on the flowing sample on a Bruker 400 MHz Avance III NMR (Billerica, MA, USA) equipped with broad band fluorine observation (BBFO) probe.…”

Coupling and optimisation of online nuclear magnetic resonance spectroscopy and mass spectrometry for process monitoring to cover the broad range of process concentration

“…The concentric design of the flow cell minimises changes in magnetic field homogeneity as the cylindrical symmetry is maintained. Commercial systems are also available; these benefit from the ability to acquire accurate kinetic data on‐flow in contrast to ‘in‐tube’ reactions as demonstrated by Foley et al In the same report, Foley et al also presented evidence for the effect of mixing on the rate of reaction determined by NMR, with the rate determined highly dependent on the NMR monitoring method used …”

Utilizing on‐ and off‐line monitoring tools to follow a kinetic resolution step during flow synthesis

“…On‐line or flow NMR spectroscopy is an attractive option for PAT because it provides detailed structural information of each of the reaction components. Historically, large reaction volumes were required with a high field NMR instrument because of the long transit from the reaction vessel to the instrument and the volume required in the NMR probe. Conversely, reactions that were miniaturized in an NMR tube for ease in reaction monitoring often did not have the ability to acquire realistic stirred batch‐like kinetic information .…”