A particularly common α-substitution reaction in the laboratory is the halogenation of aldehydes and ketones at their α positions by reaction with Cl₂, Br₂, or I₂ in acidic solution. Bromine in acetic acid solvent is often used.

Remarkably, ketone halogenation also occurs in biological systems, particularly in marine alga, where dibromoacetaldehyde, bromoacetone, 1,1,1-tribromoacetone, and other related compounds have been found.

This form of halogenation is a typical α-substitution reaction that proceeds by acid-catalyzed formation of an enol intermediate, as shown in Figure 22.4.

Figure 22.4 Mechanism of the acid-catalyzed bromination of acetone.

Evidence for the mechanism shown in Figure 22.4 includes the observation that acid- catalyzed halogenations show second-order kinetics and follow the rate law

Reaction rate = 𝑘[Ketone][H⁺]

In other words, the rate of halogenation depends only on the concentrations of ketone and acid and is independent of halogen concentration. Since halogen is not involved in the rate-limiting step, chlorination, bromination, and iodination of a given substrate all occur at the same rate.

Furthermore, if an aldehyde or ketone is treated with D₃O⁺, the acidic α hydrogens are replaced by deuterium. For a given ketone, the rate of deuterium exchange is identical to the rate of halogenation, implying that a common intermediate—presumably the enol—is involved in both processes.

α-Bromo ketones are useful in the laboratory because they can be dehydrobrominated by base treatment to yield α,β-unsaturated ketones. For example, 2-methylcyclohexanone gives 2-bromo-2-methylcyclohexanone on halogenation, and the α-bromo ketone gives 2-methyl-2-cyclohexenone when heated in pyridine. The reaction takes place by an E2 elimination pathway (Section 11.8) and is a good method for introducing a C═C bond into a molecule. Note that bromination of 2-methylcyclohexanone occurs primarily on the more highly substituted α position because the more highly substituted enol is favored over the less highly substituted one (Section 7.6).

Problem 22-4

Write the complete mechanism for the deuteration of acetone on treatment with D₃O⁺.

Problem 22-5

Show how you might prepare 1-penten-3-one from 3-pentanone.