Indirect hard modeling of low resolution benchtop NMR data for the kinetic fitting of a complex organic reaction

Abstract

Despite recent significant advances in hardware, software, and data analysis, low resolution benchtop NMRs are still underutilized for the kinetic investigation of organic reactions. Moreover, their use has typically been restricted to monitor a limited number of species with well-behaved peaks that were easily integrable. In this work, the chlorination reaction of 4-fluorothiophenol with N-chlorosuccinimide (NCS) was investigated by continuous in-line monitoring of five different reaction species through the utilization of a 43 MHz benchtop NMR instrument. The reaction was carried out under synthetically relevant conditions within different modes of operation, including re-circulating batch and single pass continuous flow mode. Quantitative concentration values could be obtained even when peaks overlapped through the use chemometric modeling, specifically indirect hard modeling (IHM). The reaction profiles were then fitted to obtain kinetic parameter estimates for a six step model structure. The study demonstrates that complex organic reactions kinetics can be explored using a low resolution NMR setup for quantitative monitoring.