Mechanistic insights into the regioselectivity in the halogenation of α-haloketones in acetic acid

Mechanistic insights into the mechanism and regioselectivity of the halogenation of α-haloketones in acetic acid were obtained with 3-chloro/bromobutan-2-ones and 2-chloro/bromocyclohexanones as model substrates. The results indicate that the enolization occurs on both α-sides of α-haloketones in acetic acid, but slightly favourably on their halogenated side in the absence of hydrogen halide, while favorably on the non-halogenated side in the presence of hydrogen halide, and the enols further undergo the almost barrierless halogenation smoothly. The enolization is the rate-determining step. During the initial enolization, two molecules of acetic acid participate to form a favorable twelve-membered cyclic transition state. After HX is generated, the enolization generally occurs through a ten-membered cyclic transition state involving acetic acid and HX predominantly. The generated hydrogen halide accelerates the halogenation and improves the regioselectivity obviously on the nonhalogenated α-carbon atom. The current investigation provides a reasonable rationale for the regioselectivity in the halogenation of α-haloketones in acetic acid.