Premium
Synthesis of α‐fluoro‐α,β‐unsaturated esters monitored by 1D and 2D benchtop NMR spectroscopy
Author(s) -
Weidener Dennis,
Singh Kawarpal,
Blümich Bernhard
Publication year - 2019
Publication title -
magnetic resonance in chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.483
H-Index - 72
eISSN - 1097-458X
pISSN - 0749-1581
DOI - 10.1002/mrc.4843
Subject(s) - deprotonation , chemistry , nuclear magnetic resonance spectroscopy , spectrometer , proton nmr , kinetics , reaction rate constant , spectroscopy , reaction mechanism , kinetic energy , analytical chemistry (journal) , organic chemistry , catalysis , ion , physics , quantum mechanics
Abstract For optimization and control of pharmaceutically and industrially important reactions, chemical information is required in real time. Instrument size, handling, and operation costs are important criteria to be considered when choosing a suitable analytical method apart from sensitivity and resolution. This present study explores the use of a robust and compact nuclear magnetic resonance (NMR) spectrometer to monitor the stereo‐selective formation of α‐fluoro‐α,β‐unsaturated esters from α‐fluoro‐β‐keto esters via deprotonation and deacylation in real time. These compounds are precursors of various pharmaceutically active substances. The real‐time study revealed the deprotonation and deacylation steps of the reaction. The reaction was studied at temperatures ranging from 293 to 333 K by interleaved one‐dimensional 1 H and 19 F and two‐dimensional 1 H– 1 H COSY experiments. The kinetic rate constants were evaluated using a pseudo first‐order kinetic model. The activation energies for the deprotonation and deacylation steps were determined to 28 ± 2 and 63.5 ± 8 kJ/mol, respectively. This showed that the deprotonation step is fast compared with the deacylation step and that the deacylation step determines the rate of the overall reaction. The reaction was repeated three times at 293 K to monitor the repeatability and stability of the system. The compact NMR spectrometer provided detailed information on the mechanism and kinetics of the reaction, which is essential for optimizing the synthetic routes for stepwise syntheses of pharmaceutically active substances.