Opposite Regiospecific Ring Opening of 2-(Cyanomethyl)aziridines by Hydrogen Bromide and Benzyl Bromide: Experimental Study and Theoretical Rationalization

Abstract

Ring opening of 1-arylmethyl-2-(cyanomethyl)aziridines with HBr afforded 3-(arylmethyl)amino-4-bromobutyronitriles via regiospecific ring opening at the unsubstituted aziridine carbon. Previous experimental and theoretical reports show treatment of the same compounds with benzyl bromide to furnish 4-amino-3-bromobutanenitriles through ring opening at the substituted aziridine carbon. To gain insights into the regioselective preference with HBr, reaction paths have been analyzed with computational methods. The effect of solvation was taken into account by the use of explicit solvent molecules. Geometries were determined at the B3LYP/6-31++G(d,p) level of theory, and a Grimme-type correction term was included for long-range dispersion interactions; relative energies were refined with the meta-hybrid MPW1B95 functional. Activation barriers confirm preference for ring opening at the unsubstituted ring carbon for HBr. HBr versus benzyl bromide ring opening was analyzed through comparison of the electronic structure of corresponding aziridinium intermediates. Although the electrostatic picture fails to explain the opposite regiospecific nature of the reaction, frontier molecular orbital analysis of LUMOs and nucleophilic Fukui functions show a clear preference of attack for the substituted aziridine carbon in the benzyl bromide case and for the unsubstituted aziridine carbon in the HBr case, successfully rationalizing the experimentally observed regioselectivity.

Synthesis of poly(2‐oxazoline)s with side chain methyl ester functionalities: Detailed understanding of living copolymerization behavior of methyl ester containing monomers with 2‐alkyl‐2‐oxazolines

“…The nature of the minima and first‐order saddle points was verified by frequency calculations. Hirshfeld‐I (HI) charges were calculated for all systems, since this charge scheme has proven useful for the analysis of the CROP of 2‐oxazolines and is relatively robust with respect to conformational changes . In order to understand the dynamic behavior of the interactions between the side chains and the cationic centre, molecular dynamics simulations were performed on a MestOx decamer with the CP2K program within an NVT ensemble using the semiempirical PM6 method.…”

ACKS2: Atom-condensed Kohn-Sham DFT approximated to second order

“…On the other hand, computational benchmarks also point out that Hirshfeld-I charges are only minimally sensitive to conformational changes (especially internal rotations), indicating the AIMs are well-localized. 33,118 Despite the encouraging computational results for the Hirshfeld-I method, a word of caution seems appropriate: most computational assessments of the Hirshfeld-I method consider organic molecules. A recent calibration of EEM and SQE parameters for silicates revealed that Hirshfeld-I charges systematically overestimate (in absolute value) the MEP of silica clusters.…”

The conformational sensitivity of iterative stockholder partitioning schemes

“…[6,12,13] It is also known that, for organic molecules, HI atomic charges accurately reproduce the ESP surrounding the molecule [14,15]. This is a distinct advantage of HI over QTAIM and implies that HI charges are both useful for a direct chemical interpretation as well as for the development of force field models.…”