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

Abstract

We report findings from the qualitative evaluation of nuclear magnetic resonance (NMR) reaction monitoring techniques of how each relates to the kinetic profile of a reaction process. The study highlights key reaction rate differences observed between the various NMR reaction monitoring methods investigated: online NMR, static NMR tubes, and periodic inversion of NMR tubes. The analysis of three reaction processes reveals that rates derived from NMR analysis are highly dependent on monitoring method. These findings indicate that users must be aware of the effect of their monitoring method upon the kinetic rate data derived from NMR analysis. Copyright © 2015 John Wiley & Sons, Ltd.

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

“…It was identified in this study that optimisation of make‐up flow composition and sample dilution factor is important in understanding reaction optimisation. This is analogous to the observations on mixing recently reported by Foley et al for online NMR experiments …”

“…The concentric design of the flow cell minimises changes in magnetic field homogeneity as the cylindrical symmetry is maintained. Commercial systems are also available [10] ; these benefit from the ability to acquire accurate kinetic data onflow in contrast to 'in-tube' reactions as demonstrated by Foley et al [11] 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. [11] A double chamber NMR tube has also been investigated by Mix and co-workers for monitoring reactions conducted in a NMR tube.…”

“…Commercial systems are also available [10] ; these benefit from the ability to acquire accurate kinetic data onflow in contrast to 'in-tube' reactions as demonstrated by Foley et al [11] 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. [11] A double chamber NMR tube has also been investigated by Mix and co-workers for monitoring reactions conducted in a NMR tube. [12] The study concludes that a 3-mm glass tube can be placed inside a 5-mm glass NMR tube with a small piece of silicone sealant; this seal then creates two compartments inside the NMR tube.…”

Gradient‐based solvent suppression methods on a benchtop spectrometer

“…Performed in an on‐line fashion, NMR provides a time resolved monitoring of the reaction progress, which is non‐destructive and suitable for almost all compounds in contrast with commonly used spectroscopies such as UV‐visible, FT‐IR or Raman. Among the different methodologies, the on‐line system in continuous flow is the most attractive one, especially compared with the case where the NMR tube is used as a reactor, which is too restrictive for numerous chemical processes …”

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

“…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 . Recently, several different vendors have introduced low field benchtop NMR instruments that can be adapted for flow reaction monitoring .…”