Abstract
Monitoring chemical reactions by nuclear magnetic resonance (NMR) is an established and valuable approach for process understanding, robustness, scalability, and control in the pharmaceutical industry. Understanding speciation, reaction rates, and reaction completion times provides information on how to improve a chemical process, leading to increased quality and quantity of the desired product. An important consideration for online monitoring is to have an NMR instrument colocated with a chemical reactor. The standard commercial medium- to high-field NMR instruments are normally installed in isolated locations due to facility and safety restrictions. Low-field NMR instruments suffer from low resolution and sensitivity, requiring chemometric analysis for medium to complex chemical structures. Reactions are typically monitored using NMR tubes and deuterated solvents. Therefore, reaction analysis may not provide the same kinetic information as when the reaction occurs in a reactor at a larger scale. To overcome these factors, we have tested a prototype NMR instrument with a 400 MHz cryogen-free power-driven high-temperature superconducting (HTS) magnet installed in a chemistry laboratory fume hood for online monitoring of reactions. We have tested the HTS NMR system with a ring-closing metathesis (RCM) reaction of diethyl diallyl malonate with Grubbs 2nd Gen catalyst in a reactor with a protonated solvent. The reaction was monitored online with a Bruker InsightMR flow cell, and data was acquired in automation, yielding a kinetic time-course of the transformation and reaction rate values. This work demonstrates that NMR instruments with HTS magnets can be integrated into the chemistry laboratory with other equipment and are a valuable tool for reaction monitoring under typical reaction conditions and in protonated solvents.
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