Stereochemical and Steric Effects in Nucleophilic Substitution of α-Halo Ketones

Abstract

Bimolecular substitution reactions of α-halo ketones with acetate and azide ions are remarkably insensitive to steric hindrance. 1-Bromo-4,4-dimethyl-2-pentanone (bromomethyl neopentyl ketone) is only slightly less reactive than bromo acetone in spite of the fact that the carbonyl group in the former is neopentylic. The results are interpreted in terms of a normal SN2 transition state, not involving either special alignment of entering and leaving group with the π-orbital of the carbonyl function (conjugation) or covalent interaction between nucleophile and carbonyl carbon (bridging) for reaction of conformation-ally-mobile systems. Conformationally-fixed systems, on the other hand, may be affected by such factors. trans,-2-Chloro-4-t-butylcyclohexanone is 61-fold more reactive than the cis-isomer, in the SN2 reaction with acetate. Activation parameters support the conclusion that only those α-halo ketones which are stereochemically set up for conjugation and bridging undergo substitution by a mechanism significantly different from that operating in corresponding reactions of alkyl halides.Possible significance of the results to the mechanism of bimolecular elimination is discussed.