Systematic Study of Halide-Induced Ring Opening of 2-Substituted Aziridinium Salts and Theoretical Rationalization of the Reaction Pathways

The ring-opening reactions of 2-alkyl-substituted 1,1-bis(arylmethyl)- and 1-methyl-1-(1-phenylethyl) aziridinium salts with fluoride, chloride, bromide and iodide in acetonitrile have been evaluated for the first time in a systematic way. The reactions with fluoride afforded regioisomeric mixtures of primary and secondary fluorides, whereas secondary beta-chloro, beta-bromo and beta-iodo amines were obtained as the sole reaction products from the corresponding halides by regio-specific ring opening at the substituted position. Both experimental and computational results revealed that the reaction outcomes in the cases of chloride, bromide and iodide were dictated by product stability through thermodynamic control involving rearrangement of the initially formed primary halides to the more stable secondary halides. The ring opening of the same aziridinium salts with fluoride, however, was shown to be mediated by steric interactions (kinetic control), with the corresponding primary beta-fluoro amines being obtained as the main reaction products. Only for 2-acylaziridinium ions was the reaction outcome shown to be under full substrate control, affording secondary beta-fluoro, beta-chloro, beta-bromo and beta-iodo amines through exclusive attack at the activated alpha-carbonyl carbon atom.