<i>N</i>‑OxideInsertion into LDADimeric Aggregates for Azomethine Ylide Formation: Explicit Solvationin Quantum Mechanical Treatment of Polarized Intermediates

The physical model used to compute natural phenomena is crucial for accurate structural and mechanism elucidation. Specifically, we examine the mechanistic consequences of an explicit LDA dimer, THF, and <i>N</i>-oxide aggregate formation at the rate-limiting step for two competing reaction pathways involving nitrogen–oxygen dissociation and alpha-hydrogen deprotonation for azomethine ylide formation. We compute the free energies of activation using the M06-2x, B3LYP, and HCTH407 functionals and second-order Møller–Plesset perturbation theory with Dunning’s correlation consistent basis sets cc-pV[D,T]Z, and corrected entropy by using Whitesides’ free volume theory. Our discrete-continuum approach uses Tomasi’s polarizable continuum model to complement the quantum system by incorporating bulk solvent effects. Building off the LDA aggregation work developed by Collum and coworkers, we demonstrate that the explicit inclusion of solvent can have a profound impact on the predicted free energy barriers and alignment with experimental product distributions. In the polarized <i>N-</i>oxide system, the use of a more sophisticated and balanced model of the reaction mechanism underscores the importance of explicit solvent and the correct pattern of aggregation. Our results identify a unique aggregate that incorporates the <i>N</i>-oxide, THF, and LDA for azomethine ylide formation, which suggests a third dimension to the John Pople diagram to enhance the accuracy through model sophistication.