Of enolate ions

Generally, methylation of enolate ions with isotopically tagged methyl iodide is a satisfactory labeling procedure. For example, application of this method has given the C-18 labeled steroids, (244) and (245) (see above), 17 -acetoxy-4jS-trideuteriomethyl-4a-methyl-l9-norandrost-5-en-3-one (264) and 19- C-testosterone acetate (268). Methylation of the anion derived from 17jS-acetoxy-4-methyl-l9-norandrost-4-en-3-one (263) with d3-methyl iodide occurs predominantly at C-4, yielding mainly the 4)S-trideuterio-methyl derivative (264) and about 10% of the corresponding C-4 epimer... 

Figure 22.5 Mechanism of enolate ion formation by abstraction of an a proton from a carbonyl compound. The enolate ion is stabilized by resonance, and the negative charge (red) is shared by the oxygen and the a carbon atom, as indicated by the electrostatic potential map.

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. 

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. 

Aldol reactions, Like all carbonyl condensations, occur by nucleophilic addition of the enolate ion of the donor molecule to the carbonyl group of the acceptor molecule. The resultant tetrahedral intermediate is then protonated to give an alcohol product (Figure 23.2). The reverse process occurs in exactty the opposite manner base abstracts the -OH hydrogen from the aldol to yield a /3-keto alkoxide ion, which cleaves to give one molecule of enolate ion and one molecule of neutral carbonyl compound. 

On the other hand, carbonyl condensation reactions require only a catalytic amount of a relatively weak base rather than a full equivalent so that a small amount of enolate ion is generated in the presence of unreacted carbonyl compound. Once a condensation has occurred, the basic catalyst is regenerated. To carry out an aldol reaction on propanal, for instance, we might dissolve the aldehyde in methanol, add 0.05 equivalent of sodium methoxide, and then warm the mixture to give the aldol product. 

In contrast to 10-104 ordinary esters react quite well, that is, two Z groups are not needed. A lower degree of acidity is satisfactory because it is not necessary to convert the attacking ester entirely to its ion. Step 1 is an equilibrium that lies well to the left. Nevertheless, the small amount of enolate ion formed is sufficient to attack the readily approachable ester substrate. All the steps are equilibria. The reaction proceeds because the product is converted to its conjugate base by the base present (that is, a P-keto ester is a stronger acid than an alcohol) ... 

Enolizable hydrogens can be replaced by deuterium (and 0 by 0) by passage of a sample through a deuterated (or 0 containing) gas chromatography column. There are many enol-keto intereonversions and acidifications of enolate ions to the keto forms listed in Organic Syntheses. No attempt is made to list them here. 

Phosphorylation of enolate ions by dialkyl or diaryl phosphorochlori-dates gives exclusive O-phosphorylation and it appears that the product geometry in acyclic systems is determined by the polarity of the solvent and... 

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... 

Still another possibility in the base-catalyzed reactions of carbonyl compounds is alkylation or similar reaction at the oxygen atom. This is the predominant reaction of phenoxide ion, of course, but for enolates with less resonance stabilization it is exceptional and requires special conditions. Even phenolates react at carbon when the reagent is carbon dioxide, but this may be due merely to the instability of the alternative carbonic half ester. The association of enolate ions with a proton is evidently not very different from the association with metallic cations. Although the equilibrium mixture is about 92 % ketone, the sodium derivative of acetoacetic ester reacts with acetic acid in cold petroleum ether to give the enol. The Perkin ring closure reaction, which depends on C-alkylation, gives the alternative O-alkylation only when it is applied to the synthesis of a four membered ring ... 

A review of aromatic substitution by the 5 rnI reaction has been published. The reactions of enolate ions of 2-acetyl-(147) and 3-acetyl-1-methylpyrroles (148) with aryl iodides and neopentyl iodides under irradiation conditions afforded good yields of substitution products by 5rn1 mechanisms, without the need for initiator. These... 

The relative reactivities of the enolate ions of acetophenone and 2-acetylnaphthalene towards phenyl radicals have been explored in order to determine their suitability as electron donor initiatiors of 5 rnI reactions of enolate ions of 2-acetylthiophene and 2-acetyl fiiran with aryl halides Phl. ... 

In order to exploit frilly the synthetic potential of enolate ions, control over the regioselectivity of their formation is required. Although it may not be possible to direct deprotonation so as to form one enolate to the exclusion of the other, experimental conditions can often be chosen to provide a substantial preference for the desired regioisomer. To understand why a particular set of experimental conditions leads to the preferential formation of one enolate while other conditions lead to the regioisomer, we need to examine the process of enolate generation in more detail. 

DMSO and /V, A- dime th y I fo nn a in i d c (DMF) are particularly effective in enhancing the reactivity of enolate ions, as Table 1.2 shows. Both of these compounds belong to the polar aprotic class of solvents. Other members of this class that are used as solvents in reactions between carbanions and alkyl halides include N-mcthyI pyrro I i donc (NMP) and hexamethylphosphoric triamide (HMPA). Polar aprotic solvents, as their name implies, are materials which have high dielectric constants but which lack hydroxyl groups or other... 

There are many enol-keto interconversions and acidifications of enolate ions to the keto forms listed in Organic Syntheses. No attempt is made to list them here. 

The chief group of compounds acidic enough to provide substantial amounts of enolate ion with ethoxide base is the p-dicarbonyl compounds. They have pK s in the... 

B Ambident Nature of Enolate Ions in Aldol Addition... 

---