Alkylation of enolate ions

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 better nucleophiles. As a result, enolate ions are more common than enols in both laboratory and biological chemistry. 

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. 

FIGURE 17.6 The electrostatic potential map of acetone enolate ion shows how the negative charge is delocalized over both the oxygen and the a carbon. 

As a result, two modes of reaction of an enolate ion with an electrophile E+ are possible. Reaction on carbon to yield an a-substituted carbonyl product is more common. 

Alkylation reactions are subject to the same constraints that affect all SjvjZ reactions (Section 12.7). Thus, the leaving group X in the alkylating agent R-X can be chloride, bromide, iodide, or tosylate. The alkyl group R should be primary or methyl and preferably should be allylic or benzylic. Secondary halides react poorly, and tertiary halides don t react at all because a competing E2 elimination of HX occurs instead. Vinylic and aryl halides are also unreac-tive because backside approach is sterically prevented. 

CHBr3 or iodoform, CHI3). Note that the second step of the reaction is a nucleophilic acyl substitution of CX3 by OH. That is, a halogen-stabilized carlniniuii acts as a leaving group. 

Problem 22.9 Why do you suppose ketone halogenations in acidic media referred to as being acid- 

One of the oldest and best known carbonyl alkvlation reactions is the malonic 

Diethyl propanedioate, commonly called diethyl malonate or malonic ester, is more acidic than monocarbonyl compounds pK =13) because its a hydrogens are flanked by two carbonyl groups. Thus, malonic ester is easih converted into its enolate ion by reaction with sodium ethoxide in ethanol. The enolate ion, in turn, is a good nucleophile that reacts rapidh with an alkyl halide to give an a-substituted malonic ester. Note in the following examples that the abbreviation Et is used for an ethyl group, CH2CH3. 

Problem 22.9 Why do you suppose ketone halogenations in acidic media referred to as being acid-catiilyzed, whereas halogenations in basic media are base-promoted In other words, why is a full equivalent of base required for halogenation  

Thomson W Click Organic Interactive to use a web-based palette to predict products in halogenation and alkylation reactions of carbonyl enolates. 

Enolates can be alkylated by reaction with alkyl halides (in an SN2 reaction with primary and secondary alkyl halides). These reactions produce new carbon-carbon bonds. 

These reactions, which involve both nucleophilic addition and a-substitu-tion steps, are amongst the most useful carbon-carbon bond-forming reactions in synthesis. 

One of the oldest and best knovm carbonyl alkylation reactions is the malonic ester synthesis, a method for preparing a carboxylic acid from an alkyl halide while lengthening the carbon chain by two atoms. 

The product of a malonic ester alkylation has one acidic a hydrogen remaining, so the alkylation process can be repeated to yield a dlalkylated malonic 

On heating with aqueous hydrochloric acid, the alkylated (or dlalkylated) malonic ester undergoes hydrolysis of its two ester groups followed by decarboxylation (loss of CO2) to yield a substituted monocarboxylic acid. 

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The rate of alkylation of enolate ions is strongly dependent on the solvent in which the reaction is carried out.41 The relative rates of reaction of the sodium enolate of diethyl n-butylmalonate with n-butyl bromide are shown in Table 1.3. Dimethyl sulfoxide (DMSO) and iV,Ai-dimethylformamide (DMF) are particularly effective in enhancing the reactivity of enolate ions. Both of these are polar aprotic solvents. Other... 

The same authors studied the stereochemistry of alkylation of 4-t-butyl-cyclohexanone. Alkylation of enolate ion 467 with triethyloxonium fluorobor-ate yielded a mixture of 0-alkyl product and approximately equal amounts of... 

Mechanism 22-4 Base-Catalyzed Keto-EnolTautomerism 1047 Mechanism 22-5 Acid-Catalyzed Keto-EnolTautomerism 1047 22-3 Alkylation of Enolate Ions 1050 22-4 Formation and Alkylation of Enamines 1051 22-5 Alpha Halogenation of Ketones 1054... 

A milder alternative to direct alkylation of enolate ions is the formation and alkylation of an enamine derivative. An enamine (a vinyl amine) is the nitrogen analogue of an enol. The resonance picture of an enamine shows that it has some carbanion character. 

Alkylation of enolate ions (Section 22.8) (a) Malonic ester synthesis... 

Alkylations of enolate ions to introduce alkyl groups to carbons adjacent to a carbonyl group (e.g., acetoacetic ester synthesis, malonic ester synthesis)... 

A stereoselective reaction leads to the exclusive or predominant formation of one of several possible stereoisomeric products. Thus, one reaction pathway from a given substrate is favored over the other (as in nucleophilic additions to cyclic ketones or alkylations of enolate ions). 

Halogenation of Enolate Ions The Haloform Reaction Alkylation of Enolate Ions 917... 

Alkylation of Enolate Ions 855 Problem 22.12 How could you use a malonic ester synthesis to prepare the following compound ... 

O-Alkylation of enolate ions by the reagent occurs to some extent in aprotic, polar solvents (1,2-dimethoxyethane), but may become the major reaction in DMSO orDMF.10... 

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