Nucleophile enolate ions

Because they re negatively charged, enolate ions act as nucleophiles and undergo many of the reactions we ve already studied. For example, enolates react with primary alkyl halides in the SK2 reaction. The nucleophilic enolate ion displaces halide ion, and a new C-C bond forms ... 

Perhaps the single most important reaction of enolate ions is their alkylation by treatment with an alkyl halide or tosylate, thereby forming a new C-C bond and joining two smaller pieces into one larger molecule. Alkylation occurs when the nucleophilic enolate ion reacts with the electrophilic alkyl halide in an SN2 reaction and displaces the leaving group by backside attack. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

Exactly the same kind of conjugate addition can occur when a nucleophilic enolate ion reacts with an ,j6-unsaturated carbonyl compound—a process known as the Michael reaction. 

Michael reactions take place by addition of a nucleophilic enolate ion donor to the /3 carbon of an a,(3-unsaturated carbonyl acceptor, according to the mechanism shown in Figure 23.7. 

A carbonyl condensation reaction takes place between two carbonyl partners and involves both nucleophilic addition and -substitution steps. One carbonyl partner (the donor) is converted by base into a nucleophilic enolate ion, which adds to the electrophilic carbonyl group of the second partner (the acceptor). The donor molecule undergoes an a substitution, while the acceptor molecule undergoes a nucleophilic addition. 

With an aromatic aldehyde as the electrophilic partner, the nucleophilic enolate ion can also be derived from a ketone or a nitrile. As illustrated in the following examples, this enables the aldol condensation to be used to form a wide variety of compounds ... 

Neither of these reactants is a strong enough nucleophile to attack the other. If ethoxide removes an a proton from methylcyclohexanone, however, a strongly nucleophilic enolate ion results. 

Only a small amount of the nucleophilic enolate ion is formed hydroxide is not basic enough to enolize an aldehyde completely. Each molecule of enolate is surrounded by molecules of the aldehyde that are not enolized and so still have the electrophilic carbonyl group intact Each enolate ion will attack one of these aldehydes to form an alkoxide ion, which will be protonated by the water molecule formed in the first step. 

When an a-substitution reaction takes place under basic conditions, a base removes a proton from the a-carbon and the nucleophilic enolate ion then reacts with an electrophile. Enolate ions are much better nucleophiles than enols because they are negatively charged. 

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. 

An alkoxide base removes an a proton from the ester, generating a nucleophilic enolate ion. (The alkoxide base used to form the enolate should have the same alkyl group as the ester, e.g., ethoxide for an ethyl ester otherwise transesterification may occur.) Although the a protons of an ester are not as acidic as those of aldehydes and ketones,... 

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