Halogenation base-catalyzed

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

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. 

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... 

Schlosser and co-workers have reported the shift of lithium in lithiated l-bromo-3-(tri-fluoromethyl)benzene 2,fa Quenching at — 100 C gives exclusively the product derived from 2, whereas after 2 hours at — 75 C, arene 2 is completely converted into less basic 3. A lithium-iodine exchange takes place in lithiated 2-chloro-3-iodo-6-(trifluoromethyl)pyridine 4, which at —85 C is totally converted into the less basic isomer 5.7 These rearrangements have been discussed in terms of a base-catalyzed halogen dance or halogen-shuffling mechanism. 

The result is that, if the monobromoketone is desired, the reaction is carried out best with an acidic catalyst rather than a basic catalyst. A further complication in the base-catalyzed halogenation of a methyl ketone is that the trihalo-ketone formed is attacked readily by base, thereby resulting in cleavage of a carbon-carbon bond ... 

Base-catalyzed displacement reactions, such as base-catalyzed halogenation, hydrogen exchange, and condensation reactions, belong to a separate class of reactions. The reactive species, in this case, is the phenolate ion rather than unionized phenol, and the reactive positions are limited to those ortho and para to the hydroxyl group. In a guaiacyl propane unit, no reaction occurs at positions 2 and 6, and displacement at position 5 will generally proceed more rapidly than the displacement of the side chain. 

In studying the base-catalyzed halogen dance, Bunnett has made the following observations. When IV is treated with QH5NHK/NH3, it is isomerized to V. There is... 

Suggest a complete mechanism for the base-catalyzed halogen dance, and show how it accounts for all the facts. It may help to go at the problem in this way. First, start with V and the base, in the presence of VI, and show how IV can be formed. Show how, under the same conditions, V can be formed from IV. 

J. F. Bunnett, The Base Catalyzed Halogen Dance, and Other Reactions of Aryl Halides, Accounts Chem. Res., 5, 139 (1972). 

As an illustration, Table I shows data for the base-catalyzed halogenation of a number of ketones and similar substances. In this table, R is the catalytic constant (in liters/mole/minute) of the anion of a hypothetical acid of dissociation constant 10-4 obtained by interpolating data for carboxylate anions. In computing R a statistical correction has been made for the number of equivalent hydrogen atoms in the substrate, counting as independent atoms attached to the same carbon. /3 is the exponent in Eq. (51). 

When applied to reactions catalyzed by acids or bases, the Bronsted relationship has a slightly different connotation. Examples of these are the base-catalyzed halogenation of ketones and esters and the acid-catalyzed dehydration of acetaldehyde hydrate. For an acid-catalyzed reaction. 

Grading the selectivity of a reagent (a carbonyi compound) for reaction between two competing bases Base-catalyzed halogenation of ketones and esters... 

Consider the base-catalyzed halogenation of ketones and esters. In this reaction there is competition for a proton between a carbonyl compound and a catalyzing base. 

Bell and co-workers (1949, 1952) reported extensive studies on the base-catalyzed halogenation of a series of ketones and esters and related the reactivity as measured by k(, with the parameter / . We know that ko has to be defined for a standard substrate. In this particular case, it is defined as the rate constant for the halogenation of a hypothetical catalyzing base with a dissociation equilibrium constant ATb of 10 . Specifically, let us demonstrate the procedure for the reagent acetone. Equation (E2.4.2) can be written as... 

As was pointed out in Part A, Section 7.3, under many conditions halogenation is fast, relative to 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 enolization and retards the rate of introduction of a second halogen on carbon. Monohalogenation can therefore usually be carried out satisfactorily in acidic solution. Base-catalyzed halogenation... 

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