Enolate ions reactions

Comparison of Reactions (A) and (C) indicates that in the conditions used, sodamide is not able to eliminate H—Br in THF and HMPA is needed to perform the reaction. However in Reaction (B), benzyne is the reaction intermediary (we shall discuss later the mechanism of formation of ketones 6 and 7) although THF is the solvent of the reaction. Also, if diethylamine is present with enolate ion [Reaction (D)] diethylaniline is formed although in THF and in the absence of enolate this product was not obtained (Reaction (C)J. From all these observations it appears that generation of benzyne in THF depends upon the nature of the nucleophile to be condensed. 

As m the acid catalyzed halogenation of aldehydes and ketones the reaction rate is mde pendent of the concentration of the halogen chlorination brommation and lodmation all occur at the same rate Formation of the enolate is rate determining and once formed the enolate ion reacts rapidly with the halogen... 

Only the a hydrogens are replaced by deuterium m this reaction The key intermediate IS the enolate ion formed by proton abstraction from the a carbon atom of cyclopen tanone Transfer of deuterium from the solvent D2O to the enolate gives cyclopentanone containing a deuterium atom m place of one of the hydrogens at the a carbon... 

The point was made earlier (Section 5 9) that alcohols require acid catalysis in order to undergo dehydration to alkenes Thus it may seem strange that aldol addition products can be dehydrated in base This is another example of the way in which the enhanced acidity of protons at the a carbon atom affects the reactions of carbonyl com pounds Elimination may take place in a concerted E2 fashion or it may be stepwise and proceed through an enolate ion... 

The nucleophilic portion of the reagent (Y m HY) becomes bonded to the p carbon For reactions carried out under conditions m which the attacking species is the anion Y an enolate ion precedes the enol... 

In practice this reaction is difficult to carry out with simple aldehydes and ketones because aldol condensation competes with alkylation Furthermore it is not always possi ble to limit the reaction to the introduction of a single alkyl group The most successful alkylation procedures use p diketones as starting materials Because they are relatively acidic p diketones can be converted quantitatively to their enolate ions by weak bases and do not self condense Ideally the alkyl halide should be a methyl or primary alkyl halide... 

Reactions of Aldehydes and Ketones That Involve Enol or Enolate Ion Intermediates... 

A reaction of great synthetic val ue for carbon-carbon bond for mation Nucleophilic addition of an enolate ion to a carbonyl group followed by dehydration of the 3 hydroxy aldehyde yields an a p unsaturated aldehyde... 

Section 21 7 The malonic ester synthesis is related to the acetoacetic ester synthesis Alkyl halides (RX) are converted to carboxylic acids of the type RCH2COOH by reaction with the enolate ion derived from diethyl mal onate followed by saponification and decarboxylation... 

Two techniques have been described for producing trimethylsilyl enol ethers from aldehydes or ketones (10) reaction of (CH2)2SiCl and (C2H3)2N in DMF and reaction of LiN(C2H3)2, which generates enolate ions in the presence of... 

A synthetically useful reaction known as the Michael reaction, or Michael addition, involves nucleophilic addition of carbanions to a,p-unsaturated ketones. The most common types of car banions used are enolate ions derived from p-diketones. These enolates are weak bases (Section 18.6) and react with a,p-unsaturated ketones by conjugate addition. 

In this paper Speziale and Smith 109) described experiments which led them to modify the mechanism proposed earlier 108) for the reaction of trivalent phosphorus compounds with haloamides. The first step is considered to be attack of the trivalent phosphorus compound on a chlorine atom of the halo amide (132) to produce a resonance-stabilized enolate ion (133). This is reasonable since under conditions where the trichloroamide... 

Propiolactone is subject to attack by enolate ions to give propionic acid derivatives of ketones. It may likewise react with nucleophilic enamines to give carboxyethylation according to the reactions. The morpholide is easily hydrolyzed to the corresponding acid. 

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 ... 

The Sn2 alkylation reaction between an enolate ion and an alkyl halide is a powerful method for making C-C bonds, thereby building up larger molecules from smaller precursors. We ll study the alkylation of many kinds of carbonyl compounds in Chapter 22. 

Although the carbonyl condensation reaction appears different from the three processes already discussed, it s actually quite similar. A carbonyl condensation reaction is simply a combination of a nucleophilic addition step and an -substitution step. The initially formed enolate ion of one acetaldehyde molecule acts as a nucleophile and adds to the carbonyl group of another acetaldehyde molecule, as shown in Figure 5. 

As noted previously, conjugate addition of a nucleophile to the j3 carbon of an cr,/3-unsaturated aldehyde or ketone leads to an enolate ion intermediate, which is protonated on the a carbon to give the saturated product (Figure 19.16). The net effect is addition of the nucleophile to the C=C bond, with the carbonyl group itself unchanged. In fact, of course, the carbonyl group is crucial to the success of the reaction. The C=C bond would not be activated for addition, and no reaction would occur, without the carbonyl group. 

Carboxylic acids having a second carbonyl group two atoms away lose C02 (clecarboxylatc) through an intermediate enolate ion when treated with base. Write the mechanism of this decarboxylation reaction using curved arrows to show the electron flow in each step. 

Because carbonyl compounds are only weakly acidic, a strong base is needed for enolate ion formation. If an alkoxide such as sodium ethoxide is used as base, deprotonation takes place only to the extent of about 0. l% because acetone is a weaker acid than ethanol (pKa - 16). If, however, a more powerful base such as sodium hydride (NaH) or lithium diisopropylamide ILiNO -CjHy ] is used, a carbonyl compound can be completely converted into its enolate ion. Lithium diisopropylamide (LDA), which is easily prepared by reaction of the strong base butyllithium with diisopropylamine, is widely used in the laboratory as a base for preparing enolate ions from carbonyl compounds. 

Many types of carbonyl compounds, including aldehydes, ketones, esters, thioesters, acids, and amides, can be converted into enolate ions by reaction with LDA. Table 22.1 lists the approximate pKa values of different types of carbonyl compounds and shows how these values compare to other acidic substances we ve seen. Note that nitriles, too, are acidic and can be converted into enolate-like anions. 

Enolate ions are more useful than enols for two reasons. First, pure enols can t normally be isolated but are instead generated only as short-lived intermediates in low concentration. By contrast, stable solutions of pure enolate ions are easily prepared from most carbonyl compounds by reaction with a strong base. Second, enolate ions are more reactive than enols and undergo many reactions that enols don t. Whereas enols are neutral, enolate ions are negatively charged, making them much belter nucleophiles. As a result, enolate ions are more common than enols in both laboratory and biological chemistry. 

As an example of enolate-ion reactivity, aldehydes and ketones undergo base-promoted o halogenation. Even relatively weak bases such as hydroxide ion are effective for halogenation because it s not necessary to convert the ketone completely into its enolate ion. As soon as a small amount of enolate is generated, it reacts immediately with the halogen, removing it from the reaction and driving the equilibrium for further enolate ion formation. 

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. 

Ethyl 3-oxobutanoate, commonly called ethyl acetoacetate or ace tome tic ester, is much like malonic ester in that its ct hydrogens are flanked by two carbonyl groups. It is therefore readily converted into its enolate ion, which can be alkylated by reaction with an alkyl halide. A second alkylation can also be carried out if desired, since acetoacetic ester has two acidic a hydrogens. 

Ketones, esters, and nitriles can all be alkylated using LDA or related dialkyl-amide bases in THE. Aldehydes, however, rarely give high yields of pure products because their enolate ions undergo carbonyl condensation reactions instead of alkylation. (We ll study this condensation reaction in the next chapter.) Some specific examples of alkylation reactions are shown. 

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