Electrophilic Substitution Alpha to Carbonyl Groups

SECTION 4.7 ELECTROPHILIC SUBSTITUTION ALPHA TO CARBONYL GROUPS 

Although the reaction of ketones and other carbonyl compounds with electrophiles such as bromine leads to substitution rather than addition, it is mechanistically closely related to electrophilic additions to alkenes. An enol or enolate derived from the carbonyl compound is the reactive species, and the initial attack is similar to the electrophilic attack 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 were discussed briefly in Part A, Chapter 7, are the most studied examples of the reaction. 

CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON-CARBON MULTIPLE BONDS 

The most common preparative procedures involve use of the halogen, usually bromine, in acetic acid. Other suitable halogenating agents include N-bromosuc-cinimide, tetrabromocyclohexadienone, and sulfuryl chloride. 

The reactions involving bromine or chlorine generate hydrogen halide and are autocatalytic. Reactions with N-bromosuccinimide or tetrabromocyclohexadienone form no hydrogen bromide and may therefore be preferable reagents in the case of acid-sensitive compounds. 

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 

Sulfur substituents can be introduced a to carbonyl groups by reaction of the enolate with a disulfide. This sulfenylation has been carried out successfully for 

The procedure has been applied to both ketones and esters. 

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The third major reaction of carbonyl compounds, alpha substitution, occurs at the position next to the carbonyl group—the alpha (a) position. This reaction, which takes place with all carbonyl compounds regardless of structure, results in the substitution of an a hydrogen by an electrophile through the formation of an intermediate enol or enolcite ion ... 

Alpha-substitution reactions occur at the position next to the carbonyl group—the a position—and involve the substitution of an cv hydrogen atom by an electrophile, E, through either an enol or eriolate ion intermediate. Let s begin by learning more about these two species. 

Carbonyl condensations are alpha substitutions where the electrophile is another carbonyl compound. If the electrophile is a ketone or an aldehyde, then the enolate ion adds to that carbonyl group in a nucleophilic addition. First, the enolate ion attacks the carbonyl group to form an alkoxide. Protonation of the alkoxide gives the addition product. 

Most reactions of carbonyl groups occur by one of four general mechanisms nucleophilic addition, nucleophilic acyl substitution, alpha substitution, am carbonyl condensation. These mechanisms have many variations, just a alkene electrophilic addition reactions and 8 2 reactions do, but the varia tions are much easier to learn when the fundamental features of the mechanisms are understood. Let s see what the four mechanisms are and what kinds of chemistry carbonyl groups undergo. 

Up to now, we have studied two of the main types of carbonyl reactions nucleophilic addition and nucleophilic acyl substitution. In these reactions, the carbonyl group serves as an electrophile by accepting electrons from an attacking nucleophile. In this chapter, we consider two more types of reactions substitution at the carbon atom next to the carbonyl group (called alpha substitution) and carbonyl condensations. 

Under basic conditions, the aldol condensation occurs by a nucleophilic addition of the enolate ion (a strong nucleophile) to a carbonyl group. Protonation gives the aldol product. Note that the carbonyl group serves as the electrophile that is attacked by the nucleophilic enolate ion. From the electrophile s viewpoint, the reaction is a nucleophilic addition across the carbonyl double bond. From the viewpoint of the enolate ion, the reaction is an alpha substitution The other carbonyl compound replaces an alpha hydrogen. 

The enhanced reactivity of the silyl- and stannyl-substituted alkenes is also favorable to the synthetic utility of carbocation-alkene reactions. Silyl enol ethers also show enhanced reactivity. Electrophilic attack is followed by desilylation to give an a-substituted carbonyl compound. The carbocations can be generated from tertiary chlorides and a Lewis acid, such as TiCU. This reaction provides a method for introducing tertiary alkyl groups alpha to a carbonyl. This transformation cannot be achieved by base-catalyzed alkylation because of the strong tendency for tertiary halides to undergo elimination. 

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