Of enolate anions

Reaction of Enolate Anions. In the presence of certain bases, eg, sodium alkoxide, an ester having a hydrogen on the a-carbon atom undergoes a wide variety of characteristic enolate reactions. Mechanistically, the base removes a proton from the a-carbon, giving an enolate that then can react with an electrophile. Depending on the final product, the base may be consumed stoichiometricaHy or may function as a catalyst. Eor example, the sodium alkoxide used in the Claisen condensation is a catalyst ... 

The reactions of ketenes or ketene equivalents with imines, discussed above, all involve the imine acting as nucleophile. Azetidin-2-ones can also be produced by nucleophilic attack of enolate anions derived from the acetic acid derivative on the electrophilic carbon of the imine followed by cyclization. The reaction of Reformatsky reagents, for example... 

The idea of kinetic versus thermodynamic control can be illustrated by discussing briefly the case of formation of enolate anions from unsymmetrical ketones. This is a very important matter for synthesis and will be discussed more fully in Chapter 1 of Part B. Most ketones, highly symmetric ones being the exception, can give rise to more than one enolate. Many studies have shown tiiat the ratio among the possible enolates that are formed depends on the reaction conditions. This can be illustrated for the case of 3-methyl-2-butanone. If the base chosen is a strong, sterically hindered one and the solvent is aptotic, the major enolate formed is 3. If a protic solvent is used or if a weaker base (one comparable in basicity to the ketone enolate) is used, the dominant enolate is 2. Enolate 3 is the kinetic enolate whereas 2 is the thermodynamically favored enolate. 

The alkylation reactions of enolate anions of both ketones and esters have been extensively utilized in synthesis. Both very stable enolates, such as those derived from (i-ketoesters, / -diketones, and malonate esters, as well as less stable enolates of monofunctional ketones, esters, nitriles, etc., are reactive. Many aspects of the relationships between reactivity, stereochemistry, and mechanism have been clarified. A starting point for the discussion of these reactions is the structure of the enolates. Because of the delocalized nature of enolates, an electrophile can attack either at oxygen or at carbon. 

One of the general features of the reactivity of enolate anions is the sensitivity of both the reaction rate and the ratio of C- versus O-alkylation to the degree of aggregation of the enolate. For example, addition of HMPA fiequently increases the rate of enolate alkylation... 

The heats of reaction for O-alkylation and C-alkylation of enolate anions clearly show that the latter reactions lead to the thermodynamically more stable products 12). 

The protonated intermediate in Eq. (5) is very reactive and could not be observed spectroscopically under the reaction circumstances. Fast hydration to isobutyraldehyde and the secondary amine occurred (75). This mechanism is exactly analogous to that of the hydrolysis of enolate anions (79), as is to be expected. 

In the alkylation of enolate anions, a mixture of mono- and polyalky lation produets is usually obtained, and when enolization of a di-a-methylene ketone is possible toward both sides, a mixture of di-a- and a,a -dialkylation products ean be expeeted. Thus the enamine alkylation sequenee beeomes partieularly attractive when eontrolled monoalkylation is imperative beeause of difficulties in separation of a mixture of alkylation produets. One of its first synthetie applications was in the reaetions of /8-tetralones with alkyl halides. Yields in exeess of 80% were usually found 238-243) in these reaetions, which make valuable intermediates for steroid and diterpene syntheses more aecessible. 

The addition of enolate anions to (E)- and (Z)-3,3,3-trifluoro-l-[(4-methylphenyl)sulfinyl]-1 -propene has been investigated (E)- and (Z)-a,/(-unsaturated sulfoxides undergo addition in the opposite stereochemical sense3,4. In general, yields and product diastereoselection are high. When the -position of the double bond of the enolate is substituted then all four diastereomer-ic products result. 

Conjugate addition of enolate anions to a, jS-unsaturated sulphoxides followed by a sulphoxide- ketone transformation were used for the preparation of 1,4-dicarbonyl compounds and cyclopentenone derivatives (equation 355)648. 

The SET mechanism is chiefly found where X = I or NO2 (see 10-104). A closely related mechanism, the SrnE takes place with aromatic substrates (Chapter 13). In that mechanism the initial attack is by an electron donor, rather than a nucleophile. The Srn 1 mechanism has also been invoked for reactions of enolate anions with 2-iodobicyclo[4.1.0]heptane. An example is the reaction of l-iodobicyclo[2.2.1]-heptane (15) with NaSnMe3 or LiPPh2, and some other nucleophiles, to give the substitution product. Another is the reaction of bromo 4-bromoacetophenone (16) with Bu4NBr in cumene. " The two mechanisms, Sn2 versus SET have been compared and contrasted. There are also reactions where it is reported that radical, carbanion, and carbene pathways occur simultaneously. ... 

If the violet color of the reaction solution is completely discharged, indicating that all the methyllithium has been consumed, addition of the enol acetate should be stopped at that point. The actual concentration of enolate anion in the solution can be calculated from the amount of enol acetate added. 

STABILIZATION OF ENOLATE ANIONS THE ENOLASE SUPER FAMILY... 

Stabilization of Enolate Anions The Enolase Super Family.173... 

Trifluoromethylation of Enolate Anions with a Suitable Combination of... 

The amount of enolate anion present at equilibrium may be calculated from the pATa values ... 

Probably the most significant examples of carbon nucleophiles are enolate anions. These can participate in a wide variety of important reactions, and simple nucleophilic substitution reactions are included amongst these. However, we shall consider these reactions at a later stage, when the nature and formation of enolate anions is discussed (see Chapter 10). 

Aldehydes and ketones nndergo acid- and base-catalysed halogenation in the a position. This is also dependent on enolization or the formation of enolate anions. 

Though this topic is treated here under a separate heading, alkylation of enolate anions is nothing other than enolate anions acting as carbanion nucleophiles in Sn2 reactions. We deferred this topic... 

We now have examples of the generation of enolate anions from carbonyl compounds, and their potential as nucleophiles in simple Sn2 reactions. However, we must not lose sight of the potential of a carbonyl compound to act as an electrophile. This section, the aldol reaction, is concerned with enolate anion... 

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