Ketones acid-catalyzed halogenation

As m the acid catalyzed halogenation of aldehydes and ketones the reaction rate is mde pendent of the concentration of the halogen chlorination brommation and lodmation all occur at the same rate Formation of the enolate is rate determining and once formed the enolate ion reacts rapidly with the halogen... 

Acid-catalyzed halogenation is synthetically useful for converting ketones to a,/3-unsaturated ketones, which are useful in Michael reactions (Section 22-18). Propose a method for converting cyclohexanone to cyclohex-2-en-l-one, an important synthetic starting material. 

The kinetics of acid-catalyzed halogenation show the rate of halogenation to be independent of halogen concentration, but dependent upon ketone concentration and acid concentration. 

Give mechanisms for acid-catalyzed and base-promoted alpha halogenation of ketones and acid-catalyzed halogenation of acids (the HVZ reaction). Explain why multiple halogenation is common with basic catalysis, and give a mechanism for the haloform reaction. 

Part of the evidence that supports these mechanisms comes from studies of reaction kinetics. Both base-promoted and acid-catalyzed halogenations of ketones show initial rates that are independent of the halogen concentration. The mechanisms that we have written are in accord with this observation in both instances the slow step of the mechanism occurs before the intervention of the halogen. (The initial rates are also independent of the nature of the halogen see Practice Problem 18.5.)... 

The required compound D could be envisaged to arise from acetylbenzene (made by Friedel-Crafts acetylation of benzene), followed by acid-catalyzed halogenation of the ketone (Section 18-3). Reduction of the nitrile group in compound C could be carried out with concomitant carbonyl conversion to give a primary amine version of compound A, namely, E. A-Methylation might be most conveniently accomplished by reductive amination (although, as we shall see in Chapter 22, the benzylic position may be sensitive to the reductive conditions employed). 

Unlike Its acid catalyzed counterpart a halogenation m base cannot normally be limited to monohalogenation Methyl ketones for example undergo a novel polyhalo genation and cleavage on treatment with a halogen m aqueous base... 

Although the reaction of ketones and other carbonyl compounds with electrophiles such as bromine leads to substitution rather than addition, the mechanism of the reaction is closely related to electrophilic additions to alkenes. An enol, enolate, or enolate equivalent derived from the carbonyl compound is the nucleophile, and the electrophilic attack by the halogen is analogous to that on alkenes. The reaction is completed by restoration of the carbonyl bond, rather than by addition of a nucleophile. The acid- and base-catalyzed halogenation of ketones, which is discussed briefly in Section 6.4 of Part A, provide the most-studied examples of the reaction from a mechanistic perspective. 

Methyl ketones are degraded to the next lower carboxylic acid by reaction with hypochlorite or hypobromite ions. The initial step in these reactions involves base-catalyzed halogenation. The a-haloketones are more reactive than their precursors, and rapid halogenation to the trihalo compound results. Trihalomethyl ketones are susceptible to alkaline cleavage because of the inductive stabilization provided by the halogen atoms. 

A ketone can be halogenated even when it isn t a methyl ketone. This process can be either acid or base catalyzed. The general mechanism is shown in Figure 11-10. 

As was pointed out in Part A, Section 7.3, under many conditions halogenation is faster than enolization. When this is true, the position of substitution in unsymmetrical ketones is governed by the relative rates of formation of the isomeric enols. In general, mixtures are formed with unsymmetrical ketones. The presence of a halogen substituent decreases the rate of acid-catalyzed enolization and therefore retards the introduction of a second halogen at the same site. Monohalogenation can therefore usually be carried out satisfactorily. A preparatively useful procedure for monohalogenation of ketones involves reaction with cupric chloride or cupric bromide.81 82 83 84 85 86... 

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