Continuous-Flow Kinetic Analysis of TBD-Catalyzed Aminolysis of d -(−)-Pantolactone Using Flow-Rate Ramping and Inline FTIR Spectroscopy

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Abstract The development of efficient and sustainable amide-bond-forming processes, together with their quantitative kinetic characterization, is of major significance to the fine chemical and pharmaceutical industries. In this study, the aminolysis of d-(−)-pantolactone (DPL) with pyrrolidine (Pyr), catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), was investigated in a continuous-flow microreactor equipped with inline Fourier transform infrared (FTIR) spectroscopy. For the first time, a flow-rate-ramp transient kinetic method was applied to an organobase-catalyzed aminolysis system. A multiresponse FTIR–PLS quantitative model was developed using Latin hypercube sampling (LHS) for calibration-set design, thereby effectively reducing the collinearity inherent in conventional calibration samples distributed along the reaction stoichiometric line. An analytical mapping between experimental time and the actual residence time of fluid elements under dynamic flow conditions was established, making it possible to extract continuous kinetic data over a residence-time range of 2–40 min from just one 83.1 min flow-rate-ramp experiment. The reaction orders with respect to DPL, Pyr, and TBD were determined to be 1, 1, and 0.85, respectively, via the isolation and initial-rate methods. An explicit analytical expression for DPL conversion was derived based on a plug-flow reactor model. Arrhenius analysis yielded an activation energy of 26.26 kJ·mol–1 and a pre-exponential factor of 2.96 × 105 L1.85·mol–1.85·min–1. The resulting model demonstrated good predictive accuracy when applied to temperatures and initial concentrations outside the fitting range. This work provides a reliable kinetic basis for the design and scale-up of continuous DPL aminolysis processes and offers a rapid and resource-efficient strategy for kinetically characterizing related metal-free organocatalytic systems.

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