Enolate ion reactivity

You have already had considerable experience with carbanionic compounds and their applications in synthetic organic chemistry The first was acetyhde ion m Chapter 9 followed m Chapter 14 by organometallic compounds—Grignard reagents for example—that act as sources of negatively polarized carbon In Chapter 18 you learned that enolate ions—reactive intermediates generated from aldehydes and ketones—are nucleophilic and that this property can be used to advantage as a method for carbon-carbon bond formation... 

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. 

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. 

There is no simple answer to this question, but the exact experimental conditions usually have much to do with the result. Alpha-substitution reactions require a full equivalent of strong base and are normally carried out so that the carbonyl compound is rapidly and completely converted into its enolate ion at a low temperature. An electrophile is then added rapidly to ensure that the reactive enolate ion is quenched quickly. In a ketone alkylation reaction, for instance, we might use 1 equivalent of lithium diisopropylamide (LDA) in lelrahydrofuran solution at -78 °C. Rapid and complete generation of the ketone enolate ion would occur, and no unreacled ketone would be left so that no condensation reaction could take place. We would then immediately add an alkyl halide to complete the alkylation reaction. 

The reaction rates for phenoxide ions are thus similar to those observed for dialkylanilines (and also enolate ions) and seem to represent an upper limit for brominating rate in aqueous solution. Consequently, the reactions have an almost zero activation energy and there is an apparent lack of deactivation by the nitro group. That bromination by BrJ occurs in this reaction is not surprising, since the high reactivity of the phenoxide ion means that it will not discriminate very much between electrophiles of differing reactivity. 

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 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. ... 

Transformation of a substrate into its ion-radical enhances the reactivity of the species. Sometimes, this can overcome steric encumbrance of the substituent to be removed. Thus, in the case of l,4-diiodo-2,6-dimethylbenzene the photoinitiated action of the enolate ion of pinaco-lone (Me3CCOCH2 ), led to substitution of both iodines (from positions 1 and 4) (Branchi et al. 

The Michael addition is an enolate ion addition to an a,(3 unsaturated Ccirbonyl. This reaction takes advantage of the increased acidity of a hydrogen atom that s a to two carbonyl groups. This enolate ion is very stable, so it s less reactive than normal enolates. The more-stable enolate leads to a greater control of the reaction so that only one or two products form instead of multiple products from a less stable (and therefore more reactive) enolate. An example of this type of reaction is in Figure 11-24 with the mechanism in Figure 11-25. 

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... 

Polar protic solvents also possess a pronounced ability to separate ion pairs but are less favorable as solvents for enolate alkylation reactions because they coordinate to both the metal cation and the enolate ion. Solvation of the enolate anion occurs through hydrogen bonding. The solvated enolate is relatively less reactive because the hydrogen-bonded enolate must be disrupted during alkylation. Enolates generated in polar protic solvents such as water, alcohols, or ammonia are therefore less reactive than the same enolate in a polar aprotic solvent such as DMSO. 

The very important reactive intermediate, the enolate ion, is an example of a Z-substituted carbanion. The charge distribution and HOMO obtained by SHMO calculation are shown below ... 

Mendez F, Gazquez JL. Chemical reactivity of enolate ions the local hard and soft acids and bases principle viewpoint. J Am Chem Soc 1994 116 9298-9301. 

The reaction rate does not vary significantly with the acidity indicating that the enols and enolate ions have about the same reactivity d Average velocity constants for the reactions of Br2 and Br, e Toullec and Dubois, 1973... 

No substitution product is formed with the enolate ion of cyclohex-2-en-l-one. However, this anion is quite reactive at the initiation step and is often used as an entrainment reagent [17]. Under photo stimulation, the best yields of heteroarylation and phenylation of the enolate ions from aromatic ketones are obtained in DMSO [18]. 

For a given aryl moiety, there is a rough correlation between the reduction potential and its reactivity in SRN1 reactions [12]. The order of reduction potential in liquid ammonia, Phi >PhBr >PhNMe3I >PhSPh > PhCl >PhF >PhOPh coincides with the reactivity order determined under photoinitiation. By competition experiments of pairs of halobenzenes toward pinacolone enolate ions under photoinitiation, the span in reactivity from PhF to Phi was found to be about 100,000 [13]. 

The factors affecting the relative reactivity of aryl halides in SrnI reactions have been analysed and compared645. Competition experiments of pairs of substrates, in photo-stimulated reactions with pinacolone enolate ion in liquid ammonia, reveal a spread of reactivity exceeding three powers of ten. The ease of formation of the radical anion of the substrate appears to dominate the overall reactivity. The rate of dehalogenation of the radical anion may become important when its stability exceeds a certain threshold. When the fragmentation rate of the radical anion intermediate is fairly slow, the overall reactivity diminishes. 

The absence of dimerization in S l reactions indicates that it is not an important termination step (equation 8), which may be related to the low concentration of the radical R in the chain reaction. However, 17% of the dimerization product 1, l -biadamantyl was found in the reaction of 1-iodoadamantane with the less reactive carbanionic nucleophiles, such as acetone enolate ion in DMSO22. Likewise, under appropriate experimental conditions, the dimerization product 4,4 -dicyanobiphenyl (39%) was the principal product of the termination step in the electrochemical induced reaction of 4-chloroben-zonitrile with 2-pyridinethiolate ions in liquid ammonia23. 

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