Dramatic Effects of Halogen Substitution and Solvent on the Rates and Mechanisms of Nucleophilic Substitution Reactions of Aziridines

Abstract

In a previous study we reported that fluorine substitution at the carbon positions of aziridine results in profound enhancements of the rate of reaction with ammonia, a typical nucleophile, in the gas phase. In this study the investigation is extended to include chloro- and bromoaziridines. Because syntheses are largely performed in the condensed phase, the present computational investigation [(MP2(Full)/6-311++G(d,p)//MP2(Full)/6-31+G(d) level] was conducted with three typical solvents that cover a wide range of polarity: THF, CH3CN, and H2O. Nucleophiles can react with haloaziridines 1 by displacing a substituted amide ion by means of an SN2 mechanism (pathway a), producing 1,2-diaminohaloethanes (from the initially formed dipolar species 2). Alternatively, a rearrangement mechanism involving rate-determining departure of a halide ion (pathway b) to form an imidoyl halide, 3, is possible. Transition-state theory was used to compute relative reaction rates of these mechanistic possibilities and to assess the role of the halogen substituents and the reaction solvent. Gas-phase results provided the basis of mechanistic insights that were more apparent in the absence of intermolecular interactions. Fluoroaziridines were found to react at accelerated rates relative to aziridine exclusively by means of the a Menshutkin-type mechanism (SN2) in each solvent tested, while the reactions of the chloro- and bromoaziridines could be directed toward 2 in the highly nonpolar solvent, cyclohexane, or toward 3 in the more polar solvents. An assessment is made of the feasibility of using this chemistry of the haloazirdines in the synthetic laboratory.

BF3·OEt2-Mediated Highly Regioselective SN2-Type Ring-Opening of N-Activated Aziridines and N-Activated Azetidines by Tetraalkylammonium Halides

“…To our delight, reaction was completed within 5 min to afford chloroamine 2a as the only product in 99% yield (Scheme ). The high regioslectivity is in accordance with the experimental , as well as extensive computational studies …”

Nucleophilic Substitution (SN2): Dependence on Nucleophile, Leaving Group, Central Atom, Substituents, and Solvent

“…Another study that showed rate acceleration with increasing ligand size was for nucleophilic substitutions at aziridine (see Scheme ). Banks used MP2 calculations to show that the activation barrier Δ H ≠ decreased from 63.4 kcal mol −1 for X=Y=H to 33.0 kcal mol −1 for X=Y=Cl, and to 31.5 kcal mol −1 for X=Y=Br.…”

Rational Design of Improved Aziridine-Based Inhibitors of Cysteine Proteases

“…Substitution of the carbon positions of the aziridine ring with fluorine, chlorine, or bromine also led to spectacularly elevated rates of ring cleavage reactions. 21,22 But also with such substitutions new reaction possibilities are opened that might decrease the inhibition potency. 22 Our first attempt advises that for an improvement of the potency on the basis of k i substituents should be used that do not open up new reaction paths.…”