Mechanisms of enol formation

We established in Chapter 12 a hierarchy for the electrophilic reactivity of acid derivatives that should by now be very familiar to you—acyl chlorides at the top to amides at the bottom. But what about the reactivity of these same derivatives towards enolization at the a position, that is, the CH2 group between R and the carbonyl group in the various structures You might by now be able to work this out. The principle is based on the mechanisms for the two processes, mechanism of nucleophilic attack mechanism of enolate formation... 

Mechanism of enol formation under both acid-catalyzed and base-catalyzed conditions, (a) Acid catalysis involves (D) initial protonation of the carbonyl oxygen followed by ( ) removal of H from the a position, (b) Base catalysis involves (Q) initial deprotonation of the a position to give an enolate ion, followed by (0) reprotonation on oxygen. 

Scheme 2.18 Mechanism of enolate formation starting from a mixed LiBr-LiNHj aggregate according to a computational study.

There have been numerous studies of the rates of deprotonation of carbonyl compounds. These data are of interest not only because they define the relationship between thermodynamic and kinetic acidity for these compounds, but also because they are necessary for understanding mechanisms of reactions in which enolates are involved as intermediates. Rates of enolate formation can be measured conveniently by following isotopic exchange using either deuterium or tritium ... 

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.

The fundamental aspects of the structure and stability of carbanions were discussed in Chapter 6 of Part A. In the present chapter we relate the properties and reactivity of carbanions stabilized by carbonyl and other EWG substituents to their application as nucleophiles in synthesis. As discussed in Section 6.3 of Part A, there is a fundamental relationship between the stabilizing functional group and the acidity of the C-H groups, as illustrated by the pK data summarized in Table 6.7 in Part A. These pK data provide a basis for assessing the stability and reactivity of carbanions. The acidity of the reactant determines which bases can be used for generation of the anion. Another crucial factor is the distinction between kinetic or thermodynamic control of enolate formation by deprotonation (Part A, Section 6.3), which determines the enolate composition. Fundamental mechanisms of Sw2 alkylation reactions of carbanions are discussed in Section 6.5 of Part A. A review of this material may prove helpful. 

The mechanism of epoxide formation (Scheme 7) has not been established but the intermediacy of nickel enolates and ensuing aldol type reactions are suspected28 (cf. Zn-mediated formation of furans from a-bromoketones29). A limitation on the synthesis is that R cannot be aryl for these cases, the products are 2,4-diarylfurans (see Section IV,B,1).30... 

Scheme 6.13 Mechanism of the formation of the/ ,y-unsaturated ketones 45 and 46 from 6 and the enolate of cyclopropyl methyl ketone.

Scheme 6.81 Mechanisms of product formation from l-oxa-2,3-cyclohexadiene (351) and enolates.

The Mechanism of the Ethyl Acetoacetate Synthesis—Before the tautomerism of ethyl acetoacetate is discussed we must consider the mechanism of its formation, which for decades has been the subject of lively discussion and was conclusively explained only in recent years (Scheibler). It has been found that even the C=0-group of the simple carboxylic esters, although in other respects inferior in activity to the true carbonyl group, can be enolised by alkali metals. Thus ethyl acetate is converted by potassium into the potassium salt of the tautomeric enol with evolution of hydrogen ... 

The mechanism of imine formation is standard, as seen in the other examples. The cyclization reaction is then like the Mannich reaction, attack of an enol on to the iminium cation. This time though, the nucleophile is provided by the resonance effect from the phenol system. 

From the base-catalyzed degradation of D-fructose (pH 8.0), Shaw and coworkers147 identified 18 compounds, none of which was (a) isomeric with the starting material, or (b) a simple dehydration product. Among the products, the hydroxy-2-butanones and 1-hydroxy-2-propanone (acetol) were shown to participate in forming the carbo-cyclic products identified, but the mechanism of their formation was not elucidated. Several furan derivatives were isolated, but no lactic acid was isolated. In a similar study but with weak acid,41 most of the products were formed by a combination of enolization and dehydration steps, with little fragmentation. 

The addition of an enolate anion to C02 to form a (3-oxoacid represents one of the commonest means of incorporation of C02 into organic compounds. The reverse reaction of decarboxylation is a major mechanism of biochemical formation of C02. The equilibrium constants usually favor decarboxylation but the cleavage of ATP can be coupled to drive carboxylation when it is needed, e.g., in photosynthesis. 

While the mechanism for cyclobutanolone formation appears to be similar to that of aliphatic diketones, the mechanism of enolization is not altogether obvious 101). It has been shown by a kinetic deuterium isotope effect that the cleavage of the C3—H bond is involved in the rate determining step. The simplest explanation, abstraction of... 

Alkylation of fl-aryleyclopentanones. Addition of 10 mole% of CuCN to the lithium enolate prepared from /3-arylcyclopentanones and LDA increases the amount of the less stable product of alkylation. Polyalkylation is also suppressed. Similar results are obtained when methyl- or phenylcopper is added to the enolate prepared by alkyUithium cleavage of trimethylsilyl enol ethers. The mechanism by which Cu(I) influences these alkylations is not as yet understood. The regiospecificity of enolate formation in the example Illustrated in equation (I) has been attributed to a directing efiect of the proximate phenyl group. This effect is also observed in the deprotonation of -arylcyclohexanones. Quantitative, but not qualitative, differences exist between five- and six-membered rings, probably because of conformational differences. ... 

The proposed mechanism involves a preequilibrium of enolate formation (HBO ") followed by a rate-determining electron transfer ... 

Mechanism of enolate ion formation by abstraction of an a proton from a carbonyl... 

The stereoselection in the cyclization of each diastereomer was examined independently. The stereochemical outcome of the cyclization should be predictable based on our assumption regarding the relationship between enolate stereochemistry and cyclopropane stereochemistry, the principles of asymmetric, intermolecular alkylation of optically active amides (9-13) and the assumption that the mechanism of cyclopropane formation involves a straightforward back-side, %2 reaction. In the case of the major diastereomer, the natural tendency of the enolate to produce the cis-cyclopropane will oppose the facial preference for the alkylation of the chiral enolate. Consequently, poorer stereochemical control would be ejected in the ring closure. In the minor diastereomer these two farces are working in tandem, and high degrees of stereocontrol should result. 

In an interesting paper, Sutin and co-workers [97] have reported a detailed investigation of the kinetics and mechanism of the formation of the monothenoyltrifluoroacetone complex of Ni(II) (and Co(II) and Cu(II)) by stopped-flow spectrophotometry. The major species present in aqueous solution of the 3-diketone is the keto hydrate although this form is not reactive towards the metal ion. Complex formation occurs exclusively via the enol form, the rate law indicating parallel acid-independent and inverse-acid routes as shown in the scheme... 

The mechanism of the formation of 24 is unknown, however, one possible explanation would be either the formation of aminal 25 or enol ether 26 as intermediates in the presence of an alcohol, followed by a reaction with 1,2-disubstituted hydrazine to form intermediates 27 and 28, which cyclize into 24 (Scheme 11). 

The third pattern of reaction of sulphonium ylides with alkynes results in the formation of furans. For example, the reaction which afforded (47) and (48) in benzene gave the furan (49) in high yield when DMSO was used as solvent. Furthermore, warming (47) in ethanol or DMSO effects conversion into the furan (49), perhaps indicating the actual mechanism of furan formation (i.e. enolate anion displacement of the sulphonium group). In this type of reaction, the acetylenic carbon atoms become C-3 and C-4 of... 

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