Quantitation of a Ketone Enolization and a Vinyl Sulfonate Stereoisomer Formation Using Inline IR Spectroscopy and Modeling

This study uses infrared (IR) spectroscopy to achieve process understanding during the synthesis of a tetrasubstituted acyclic olefin via ketone enolization and tosylation. ReactIR, an inline Fourier transform IR immersion probe, was used to monitor ketone enolate formation and tosylation in a two-step, one-pot reaction. A quantitative univariate model was constructed from the ketone carbonyl IR peak height of the starting material. This model was used to determine the rate of consumption of the starting material and to establish end points for various reaction conditions. For the second step of the reaction, the vinyl sulfonate formation, the entire IR spectrum was analyzed and offline HPLC data were collected to measure the ratio of E versus Z tetrasubstituted vinyl tosylate products. Principal component analysis and partial least-squares regression were employed to build a multivariate model that was then used to quantify and predict the relative amount of E and Z stereoisomers in situ. Sensitivity and applicability of the models were then validated using reaction data acquired across a variety of experimental conditions.