Integrated Reaction Monitoring and In Situ Structural Elucidation of Reactive Intermediates With Time-Resolved NOAH NMR Supersequences.

Structural elucidation of reaction intermediates and side products is often key to mechanistic understanding. However, individual isolation of these species is time-consuming, labor-intensive, and often technically challenging, if not impossible. Here, we present an NMR experimental workflow involving the time-resolved acquisition and processing of multiple types of two-dimensional NMR spectra acquired in tandem using NOAH supersequences on an active reaction. This time-resolved NOAH nonuniform sampling method (TR-NOAH-NUS) enables the generation of robust concentration-time plots for kinetic analysis in parallel to structural characterization of reaction components. Here, we demonstrate the application of TR-NOAH-NUS on an organo-catalyzed acylation of alcohols. Despite the short (30 min) timespan of the reaction, we are able to obtain high-quality HSQC, HMBC, and COSY spectra with excellent (less than 15 s) temporal resolution. From these data, we can observe both an on-cycle catalytic intermediate and an off-cycle catalyst degradation product and can directly assign the structures of both without need for further isolation.