Intramolecular π−π Stacking Interactions in 2-Substituted N,N-Dibenzylaziridinium Ions and Their Regioselectivity in Nucleophilic Ring-Opening Reactions

Abstract

The ring opening of 2-substituted N,N-dibenzylaziridinium ions by bromide is known to occur exclusively at the substituted aziridine carbon atom via an S N 2 mechanism, whereas the opposite regioselectivity has been observed as the main pathway for ring opening by fluoride.Similarly, the hydride-induced ring opening of 2-substituted N,N-dibenzylaziridinium ions has been shown to take place solely at the less hindered position. In order to gain insight into the main factors causing this difference in regioselectivity, a thorough and detailed computational analysis was performed on the hydride and halide-induced ring openings of 1-benzyl-1-(α-(R)-methylbenzyl)-2(S)-(phenoxymethyl)aziridinium bromide. Intramolecular π-π stacking interactions in the aziridinium system were investigated at a range of levels that enable a proper description of dispersive interactions; a T-stacking conformer was found to 2 be the most stable. Ring opening mechanisms were investigated with a variety of DFT and high level ab initio methods to test the robustness of the energetics along the pathway in terms of the electronic level of theory. The necessity to utilize explicit solvent molecules to solvate halide ions was clearly shown; the potential energy surfaces for non-solvated and solvated cases differed dramatically. It was shown that in the presence of a kinetically viable route, product distribution will be dictated by the energetically preferred pathway; this was observed in the case of hard nucleophiles (both hydride donors and fluoride). However, for the highly polarizable soft nucleophile (bromide), it was shown that in the absence of a large energy difference between transition states leading to competing pathways, the formation of the thermodynamic product is likely to be the driving force. Distortion/interaction analysis on the transition states has shown a considerable difference in interaction energies for the solvated fluoride case, pointing to the fact that sterics plays a major role in the outcome, whereas for the bromide this difference was insignificant, suggesting bromide is less influenced by the difference in sterics.

Insight in the activity and diastereoselectivity of various Lewis acid catalysts for the citronellal cyclization

“…In the case of ATPH, the M06-2X hybrid functional [54,55] is a good choice to accurately quantify the adsorbate-ligand interactions and ligand-ligand interactions because it is used especially for medium range non-covalent interactions. In this functional, double Hartree−Fock exchange is included to improve the description of non-covalent interactions [56,57]. Furthermore, the double-zeta Pople basis set 6-311+g(d,p) was applied for subsequent energy refinements in case of ATPH.…”

Synthesis of 2-(aminomethyl)aziridines and their microwave-assisted ring opening to 1,2,3-triaminopropanes as novel antimalarial pharmacophores

“…In contrast to their activated counterparts, non-activated aziridines have been evaluated to a limited extent up to now, both from a synthetic and a pharmacological point of view. Due to the presence of an electron-donating substituent at nitrogen, the latter aziridines have to be activated toward aziridinium ion intermediates prior to ring opening [18,19,20,21,22,23,24,25,26,27,28,29,30,31]. Within the present work, the scarcely studied subclass of non-activated 1-alkyl-2-(aminomethyl)aziridines [32,33,34,35,36,37,38,39] was employed as a source of substrates for the development of a novel entry toward the biologically relevant 1,2,3-triaminopropane unit through a highly regioselective and microwave-assisted ring opening by diethylamine in acetonitrile.…”

Competitive Reactions of Organophosphorus Radicals on Coke Surfaces

“…[44,48,[68][69][70][71][72][73][74][75][76][77] In an effort to account for dispersive interactions between the coke surface and aromatic rings of the radicals studied herein, the newly developed density functional M06-2X, shown to correctly predict p-p stacking interactions, was utilized. [68,70] Recent computational studies on aromatic dimers have shown that T-shaped and parallel-displaced configurations are nearly isoenergetic and are the most favorable among interactions between aromatic moieties. [78][79][80] In light of this, several types of stacking interactions between the coke models and the aromatic substituents of the radicals were taken into consideration.…”

“…[26] p-p stacking in radical addition reactions with benzene: To probe the effect of stacking in radical reactions on coke surfaces, addition of representative aromatically substituted radical 2 on benzene was investigated. Stacked and nonstacked conformations of the addition transition states for radical 2 (2-add-stacked-TS and 2-add'-TS, respectively), optimized at the M06-2X/6-31 + GA C H T U N G T R E N N U N G (d,p) level of theory, used extensively in recent computational studies involving organic reactions with dispersive effects, [68,77,81] are depicted in Figure 2. A parallel-displaced conformation between the surface model benzene and one of the aromatic radical substituents (displaced 20.18 and 3.608 from center to center) can be seen in the case of 2-add-stacked-TS.…”