Halogenation of ketones

A commonly used alternative to the direct bromination of ketones is the halogenation of enol acetates. This can be carried out under basic conditions if necessary. Sodium acetate, pyridine or an epoxide is usually added to buffer the reaction mixture. The direction of enolization is again dependent upon considerations of thermodynamic and kinetic control therefore, the proportion of enol acetates formed can vary markedly with the reaction conditions. Furthermore, halogenation via enol acetates does not necessarily give the same products as direct halogenation of ketones 3. 23... 

General base catalysis is catalysis by a Br nsted base acting by accepting a proton. The halogenation of ketones, a reaction discussed in Section 5.3, is general base catalyzed. 

Apply the steady-state approximation to the general base-catalyzed halogenation of ketones ... 

The reaction shows a first-order dependence on substrate concentration but, except at very low concentration, is zero-order with respect to oxidant moreover, the zero-order rate coefficient is the same as that observed with oxidations by iodine, cupric chloride and silver nitrate. The reaction is acid-catalysed. The oxidation is completely analogous to the halogenation of ketones and involves a slow tautomeric equilibrium followed by rapid oxidation, viz. 

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. 

Instead of direct halogenation of ketones, reactions with more reactive derivatives such as silyl enol ethers and enamines have advantages in certain cases. 

The halogenation of ketones is also catalysed by acids (general acid catalysis, cf. p. 74), the rate law observed is,... 

In this respect such reactions are analogous to the S 1 or limiting reactions of compounds producing carbonium ions, although the intermediate is a solvated carbanion rather than a solvated carbonium ion. In the base-catalyzed halogenation of ketones, for example, the rate is independent of the halogen concentration and is the same for the reaction with bromine as for the reaction with chlorine.384... 

Successful solutions to the a-halogenation of ketones have also emerged, but here the problem is that sterically very hindered catalysts that work very nicely with aldehydes are not active with ketones. Some current solutions to this problon are summarized in Scheme 31 [314,317,318]. 

In the latest development of his elegant work with hydrazone derivatives, Andrew Myers of Harvard reports (J. Am. Chem. Soc. 2004,126, 5436) that Sc(OTf), catalyzes the addition of l,2-bis(r-butyldimethylsilyl)hydrazine, to aldehydes and ketones to form the t-butyldimethylsilylhydrazones. Addition of tBuOH/tBuOK in DMSO to the crude hydrazone effects low temperature Wolff-Kishner reduction. Alternatively, halogenation of ketone hydrazones can lead to vinyl halides such as 11, or the 1,1-dihalo derivatives, depending on conditions. Halogenation of aldehyde hydrazones provides the 1,1-dihalo derivatives such as 13. 

The previous discussion of the halogenation of ketones is incomplete in one important respect concerning base-induced halogenation. That is, once an a-halo ketone is formed, the other hydrogens on the same carbon are rendered more acidic by the electron-attracting effect of the halogen and are replaced much more rapidly than the first hydrogen ... 

Halogenation of ketones, 275 Hemi-orthoester, 63 Hemi-orthoamide, 103-105 Hemi-orthothioamide, 144 Hemi-orthothiol esters, 93-97 Hinesol, 250... 

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