Base-promoted halogenation of ketones

Problem 21.5 Show in detail exactly how each of the following facts provides evidence for the carbanion mechanism of base-promoted halogenation of ketones. 

Two factors could contribute to the observed regiochemistry of base-promoted halogenation of ketones. One is a kinetic preference for formation of the less substituted enolate. Evidence for this effect can be seen in the rate constants for base-catalyzed iodination of phenyl alkyl ketones with the structure C6H5COCHR1R2, which are found to decrease with increasing alkyl substitution (Table 7.8). ... 

A second possible explanation for the regiochemistry of base-promoted halogenation of ketones is a greater thermodynamic stability of the less substituted enolate, and there is evidence suggesting that this may be the case for some enolates. House and Kramar investigated the equilibria... 

Substituent effects on rate constants of base-promoted ionisation of ketones have led to the conclusion that an electron-withdrawing substituent increases the rate of ionisation, in agreement with the anionic character of the transition state. This is based chiefly on studies on halogenation and isotope exchange of aromatic ketones. Data on p-values observed by plotting ionisation rate constants versus Hammett -parameters (Table 3) for substituted... 

Base-promoted halogenation of aldehydes and ketones is little used ir, practice because it s difficult to stop the reaction at the monosubstituted product. An -halogenated ketone is generally more acidic than the star ing, unsubstituted ketone because of the electron-withdrawing inductiv effect of the halogen atom. Thus, monohaiogenated products are themselvi rapidly turned into enoiate ions and further halogcnated. 

Base-promoted halogenation of methyl ketones leads to an interesting result known as the haUtform reaction (See Exercises.). 

Base-promoted halogenation of a methyl ketone (or aldehyde) gives rise to the following... 

Mechanism 22-6 Base-Promoted Halogenation 1054 Mechanism 22-7 Final Steps of the Haloform Reaction 1056 Mechanism 22-8 Acid-Catalyzed Alpha Halogenation 1058 22-6 Alpha Bromination of Acids The HVZ Reaction 1059 22-7 The Aldol Condensation of Ketones and Aldehydes 1060... 

The base-promoted halogenation takes place by a nucleophilic attack of an enolate ion on the electrophilic halogen molecule. The products are the halogenated ketone and a halide ion. 

Because of this tendency for multiple halogenation, base-promoted halogenation is rarely used for the preparation of monohalo ketones. The acid-catalyzed procedure (discussed in Section 22-5C) is preferred. 

Addition of an Enolate to Ketones and Aldehydes (a Condensation) 1046 Substitution of an Enolate on an Ester (a Condensation) 1046 Base-Catalyzed Keto-EnolTautomerism 1047 Acid-Catalyzed Keto-EnolTautomerism 1047 Base-Promoted Halogenation 1054 Final Steps of the Haloform Reaction 1056 Acid-Catalyzed Alpha Halogenation 1058 Acid-Catalyzed Aldol Condensation 1063 1,2-Addition and 1,4-Addition (Conjugate Addition) 1085... 

Acids, like bases, speed up the halogenation of ketones. Acids are not, however, consumed, and hence we may properly speak of Sicid-catalyzed halogenation (as contrasted to basQ-promoted halogenation). Although the reaction is not. 

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. 

In contrast, base-promoted halogenation tends to occur on the less substituted a carbon atom. For example, base-promoted iodination of methyl alkyl ketones leads initially to the iodomethyl alkyl ketone. Further reaction leads to the a,a-diiodo-, then to the a,a,a-triiodoketone, and then to iodoform and a carboxylate ion by the haloform reaction (Figure 7.10). 

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.)... 

PRACTICE PROBLEM 18.4 Why do we say that the halogenation of ketones in a base is base promoted rather than... 

Generally, isolated olefinic bonds will not escape attack by these reagents. However, in certain cases where the rate of hydroxyl oxidation is relatively fast, as with allylic alcohols, an isolated double bond will survive. Thepresence of other nucleophilic centers in the molecule, such as primary and secondary amines, sulfides, enol ethers and activated aromatic systems, will generate undesirable side reactions, but aldehydes, esters, ethers, ketals and acetals are generally stable under neutral or basic conditions. Halogenation of the product ketone can become but is not always a problem when base is not included in the reaction mixture. The generated acid can promote formation of an enol which in turn may compete favorably with the alcohol for the oxidant. 

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