A MEDT computational study of the mechanism, reactivity and selectivity of non-polar [3+2] cycloaddition between quinazo
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ORIGINAL PAPER
A MEDT computational study of the mechanism, reactivity and selectivity of non-polar [3+2] cycloaddition between quinazoline-3-oxide and methyl 3-methoxyacrylate Abdelmalek Khorief Nacereddine 1 Received: 20 July 2020 / Accepted: 22 October 2020 / Published online: 4 November 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract The Molecular Electron Density Theory (MEDT) was used for the study of the mechanism and the selectivity of the [3+2] cycloaddition reaction between quinazoline-3-oxide and methyl 3-methoxyacrylate, using the B3LYP/6-31G(d,p) DFT method. In gas phase, this [3+2] cycloaddition reaction is characterized by a completely ortho regioselectivity and a moderate exo stereoselectivity. Dichloroethane solvent did not modify the selectivities obtained in gas phase but increase the activation energies and decrease the exothermic character. Analysis of thermodynamic characters indicates that by the inclusion of the experimental conditions, the reaction becomes endergonic and thereby under thermodynamic control favouring the formation of the most stable product as observed experimentally, explaining the exo stereoselectivity. The analysis of the global electron density transfer (GEDT) at the transition states and bond order (BO) show that this reaction takes place via a very slightly synchronous and non-polar one-step mechanism. Conceptual DFT reactivity indices analysis accounts for the electrophilic character of the reagents, explaining the high obtained free activation energies, while local Parr functions analysis allows us to explain the ortho regioselectivity observed experimentally. ELF topological analysis of the most favoured reactive pathways indicates that mechanism of this 32CA reaction is one stage, one step, synchronous and non-concerted. The stability of the favourable cycloadduct is attributed to the presence of different non-conventional hydrogen bonds interactions as indicated by NCI and QTAIM analyses. Keywords Mechanism . Reactivity . Selectivity . Cycloaddition . DFT calculations . MEDT
Introduction Quinazolines are very important structures, which were found in a tremendous biological active molecules displaying a vast spectrum of pharmacological properties [1–5]. Likewise, isoxazolidines are also a very important heterocyclic molecules having a large broad potential biological and medicinal activities [6, 7].
Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s00894-02004585-0. * Abdelmalek Khorief Nacereddine [email protected]; [email protected] 1
Laboratory of Physical Chemistry and Biology of Materials, Department of Physics and Chemistry, Higher Normal School of Technological Education-Skikda, Azzaba, Skikda, Algeria
The link of two biological active compounds is an important modern strategic synthetic technique, which is used for enhancing the primary pharmacological properties. Thereby, the link between quinazoline and isoxazolidine scaffolds produce a new typ
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