Reaction NMR: A Quantitative Kinetic Analysis "Probe" for Process Development

Reaction NMR combines the power of NMR spectroscopy with lab-scale reactors targeting reactions with kinetic time-scales on the order of seconds to minutes. Long reactions on the order of hours can simply be run in an NMR tube and followed with time in the traditional way. Reactions with time scales on the order of several seconds to minutes, however, can pose challenges to elucidate the kinetic pathways with conventional techniques. Even when those techniques are specific to the functional groups in question, quantitation and complete mass balance can often be challenging in a complex reaction mixture. NMR offers a multidimensional approach to following reaction - via multiple nuclei to follow 1H, 13C, 19F, 31P and is convenient for extracting molar concentrations needed for achieving mass balance. The project that will be discussed was a collaboration with Bruker BioSpin. We will discuss the design of a prototype NMR flow cell with multinuclear capability and the thermostated interface between NMR and lab reactor. A brief overview of the design as well quantitative kinetic results from chemical reaction steps in pharmaceutical process development will be discussed.