Alternative Non-Ionic Pathway for Uncatalyzed Prins Cyclization: DFT Approach

Abstract

Density functional theory calculations (ωB97X-D/6-311++G(d,p)) are employed to investigate an alternative pathway for Prins-like cyclization. Although strong acids usually catalyze this reaction, 4-amino-1,3-dioxanes are rapidly obtained in high yields without catalyst when benzenamines and acetaldehyde react at low temperatures, in aqueous medium. Considering these conditions, we applied a supermolecule model with explicit water molecules to compute the mechanism for 4-amino-1,3-dioxanes formation from the reactants. The structure of the primary solvation shell was determined by Metropolis Monte Carlo method. In the Prins-cyclization step, we found an unpredicted pathway with non-ionic transition structures or intermediates. Explicit water molecules establish a net of hydrogen bonds allowing prototropism, maintaining the electrical neutrality in the system while two protons transfer occurs. To provide data to further experimental confirmation of this hypothesis, we estimated the kinetic isotope effect for the reaction. We also investigated the use of aliphatic amines, which indicates that the reaction may be of a broader application than first observed experimentally.

Going beyond structural effects: explicit solvation influence on the rotational isomerism of C-glycosylated flavonoids

“…The solvent arrangement around the solute can be obtained by a top-down approach starting with a condensed phase simulation (using molecular dynamics or Monte Carlo calculations), and only a few explicit solvent molecules are selected for a DFT level evaluation. 23,26,63,64 Herein, we combine both models, known as the hybrid cluster-continuum model, to simulate solvent effects (DMSO and H 2 O) on the rotational isomerism. We chose the simulated solvent compatible to experimental available data.…”

“…Computational evaluations have indicated that incorporating explicit solventsolute interactions in simulations can result in distinct chemical phenomena, including changes in reactivity, types of reaction mechanisms, and isomerism. [23][24][25] Herein, we employed for the first time Density Functional Theory (B3LYP-D3/6-311++G(d,p)) to investigate how the substituents and the solvent affect the rotational isomerism in C-glycosyl flavonoids. This quantum method can access the transition state of bond rotation and dispersive interactions along the flavonoid backbone that can influence the isomerism.…”

Exploring borderline SN1–SN2 mechanisms: the role of explicit solvation protocols in the DFT investigation of isopropyl chloride

“…, 3–4 Å) or based to the radial pair distribution function, to be evaluated at the quantum level. 4,17–20 In the bottom-up approach, explicit solvent molecules are added one by one around the substrate, seeking stable interactions based on the user's chemical intuition or molecular electrostatic potential analysis. 16,21–25…”

“…20 In both cases, the authors determined the number of water molecules based on the radial pair distribution function. 19,20…”

“…This mechanism is only assessable by explicitly simulating the solvent molecules. 19 Pereira also employed this stochastic generation of solvent configurations to investigate the mechanism for the alkaline hydrolysis of phosphoranes. 20 In both cases, the authors determined the number of water molecules based on the radial pair distribution function.…”