Thermodynamic enolate, formation

Formation of Enol Trifluoromethanesulfonates (Enol Triflates). Kinetic or thermodynamic enolate formation, through reaction of unsymmetrical ketones with properly selected strong bases, followed by treatment with Tf2NPh provides regioselective... 

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 ... 

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 preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

It is important to perform both the Birch reduction of 5 and the alkylation of enolate 6 at —78 °C. Enolate 6 obtained directly from 5 at low temperatures is considered to be a kinetic enolate . A thermodynamic enolate obtained from 6 by equilibration techniques has been shown to give an opposite sense of stereoselection on alkylation. Although a comprehensive study of this modification has not been carried out, diastereoselectivities for formation of 8 were found to be greater than 99 1 for alkylations with Mel, EtI, and PhCH2Br. Thus, it should be possible to obtain both enantiomers of a target structure by utilization of a single chiral benzamide. SE... 

By adjusting the conditions under which an enolate mixture is formed from a ketone, it is possible to establish either kinetic or thermodynamic control. Ideal conditions for kinetic control of enolate formation are those in which deprotonation is rapid, quantitative,... 

For many ketones, stereoisomeric as well as regioisomeric enolates can be formed, as is illustrated by entries 6, 7, and 8 of Scheme 1.3. The stereoselectivity of enolate formation, under conditions of either kinetic or thermodynamic control, can also be controlled to some extent. We will return to this topic in more detail in Chapter 2. 

The use of /i-ketocstcrs and malonic ester enolates has largely been supplanted by the development of the newer procedures based on selective enolate formation that permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of ketoesters intermediates. Most enolate alkylations are carried out by deprotonating the ketone under conditions that are appropriate for kinetic or thermodynamic control. Enolates can also be prepared from silyl enol ethers and by reduction of enones (see Section 1.3). Alkylation also can be carried out using silyl enol ethers by reaction with fluoride ion.31 Tetraalkylammonium fluoride salts in anhydrous solvents are normally the... 

When a catalytic amount of base is used, the reaction proceeds with thermodynamic control of enolate formation. The most effective nucleophiles under these conditions are carbanions derived from relatively acidic compounds such as /i-kctocstcrs or malonate esters. The adduct anions are more basic and are protonated under the reaction conditions. Scheme 1.11 provides some examples. 

Under conditions for thermodynamic control, the major regioisomer formed is usually the enolate Carrying most substituents at the double bond. This can be attributed to the fact that the stability of C-C double bonds increases with increasing substitution6. Conditions for kinetic control in enolate formation usually favor formation of the enolate with the least substituents at the double bond. The rational for this is based on steric reasons, i.e., the less hindered proton is abstracted more rapidly than the hindered proton, giving the less substituted enolate. 

Scheme5.4. Enolate formation under kinetic and thermodynamic...

Another important contribution is to the regioselectivity of enolate formation from unsym-metrical ketones. As we established in chapter 13, ketones, particularly methyl ketones, form lithium enolates on the less substituted side. These compounds are excellent at aldol reactions even with enolisable aldehydes.15 An application of both thermodynamic and kinetic control is in the synthesis of the-gingerols, the flavouring principles of ginger, by Whiting.16... 

The review starts with a discussion of the mechanism of keto-enol tautomerisation and with kinetic data. Included in this section are results on stereochemical aspects of enolisation (or enolate formation) and on regioselec-tivity when two enolisation sites are in competition. The next section is devoted to thermodynamic data (keto-enol equilibrium constants and acidity constants of the two tautomeric forms) which have greatly improved in quality over the last decade. The last two sections concern two processes closely related to enolisation, namely the formation of enol ethers in alcohols and that of enamines in the presence of primary and secondary amines. Indeed, over the last fifteen years, data have shown that enol-ether formation and enamine formation are two competitive and often more favourable routes for reactions which usually occur via enol or enolate. 

Enolisation and ionisation are also the first stages of some elimination reactions, aldolisation, alkylation, etc., but in most cases the enolisation (or ionisation) process is not rate-limiting. Thermodynamic data on enol and enolate formation are needed to understand the kinetic behaviour of these reactions, but a complete picture must include data on the subsequent steps. 

In constrast, kinetic regioselectivity does not usually correspond to the thermodynamic stability ratio between the two enolates. Indeed, when the ketone is ionised in protic solvents which make equilibration possible, the more substituted enolate is formed (e.g. [45] and [46] are in the ratios 10 90 and 40 60 for the lithium and sodium ion pairs, respectively, in dimethyl ether) (House, 1972). This means that the hyperconjugative effect, which is predominant in the enolate, is less important than inductive and steric effects in the transition state, a result which is in agreement with the carbanion character. The regioselectivity of preparative enolate formation in organic solvents has been reviewed by D Angelo (1976). 

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