Computer-aided kinetic network modeling of orthoester metathesis

Abstract

Dynamic covalent exchange (DCE) reactions often generate complex mixtures that make quantitative analysis challenging despite involving mechanistically simple individual processes. Here we introduce an integrated workflow combining automated spectral decomposition, mechanistically guided kinetic modeling, and targeted DFT calculations to elucidate the DCE between triethyl orthoformate and ethylene glycol. Tensor-based analysis of time-resolved ¹H NMR data identified ten distinct species, which were incorporated into a refined kinetic model providing excellent agreement with experiments (R² > 0.95) and strong predictive performance under various conditions (R² > 0.90). DFT calculations focused on the acid-promoted activation step supported the kinetic parameters and clarified how substrate structure, catalyst identity, solvent, and released alcohols influence activation barriers and catalyst availability. Together, these results deliver a coherent description of the reaction network and establish a generalizable strategy for analyzing and tuning complex dynamic covalent systems.