Real-Time Reaction Monitoring of Azide–Alkyne Cycloadditions Using Benchtop NMR-Based Signal Amplification by Reversible Exchange (SABRE)

Abstract

Rufinamide, possessing a triazole ring, is a new antiepileptic drug (AED) relatively well-absorbed in the lower dose range (10 mg/kg per day) and is currently being used in antiepileptic medications. Triazole derivatives can interact with various enzymes and receptors in biological systems via diverse non-covalent interactions, thus inducing versatile biological effects. Strain-promoted azide–alkyne cycloaddition (SPAAC) is a significant method for obtaining triazoles, even under physiological conditions, in the absence of a copper catalyst. To confirm the progress of chemical reactions under biological conditions, research on reaction monitoring at low concentrations is essential. This promising strategy is gaining acceptance for applications in fields such as drug development and nanoscience. We investigated the optimum Ir catalyst and magnetic field for achieving maximum proton hyperpolarization transfer in triazole derivatives. These reactions were analyzed using signal amplification by reversible exchange (SABRE) to overcome the limitations of low sensitivity in nuclear magnetic resonance spectroscopy, when monitoring copper-free click reactions in real time. Finally, a more versatile copper-catalyzed click reaction was monitored in real time, using a 60 MHz benchtop NMR system, in order to analyze the reaction mechanism.

Perspectives on Nuclear Magnetic Resonance Spectroscopy in Drug Discovery Research

“…They have found uses for reaction monitoring, chemical analysis, and quantification and analysis of metabolite profiles among others. An inspection of recently published articles shows benchtop NMR data contributing to the quantification of oxidation products, 123 mechanistic insights of synthetic reactions (Figure 33), 124 cycloaddition reaction monitoring, 125 and complex biofluid mixture analysis. 126 Throughout this perspective, we see that numerous NMR workflows are underpinned by computational methods to accelerate data analysis.…”