Enolate anions formation, kinetic control

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. 

Whatever the explanation, the effect of acids is less marked than the selectivffy in alkaline solutions, where a attack is largely suppressed. The effect of alkali may depend upon the formation and selective reduction of enolate anions. The A2 4-dienolate anion, which is the major product of kinetically-controlled enolisation by bases (see p. 156) is seen from a molecular model to have a somewhat "folded conformation of the A/B ring system (ii). The convex / -face of the A/B ring system and the absence of an axial 2jS-proton should favour approach to the catalyst from this direction, whereas the a-face of the A -bond is severely hindered by the axial hydrogens at C(7) and C<9>. 

The palladium catalyst generally used is Pd(PPhj)4, which can be formed in situ from Pd(OAc)2 and PPhj. The most often used allylic substrates are those having an ester or a carbonate as a leaving group, although -OPO(OR)2, -OPh, -Cl, or -Br will also work. Soft nucleophiles of the malonate-type generally give the best results for carbon-carbon bond formation. The reaction is usually in eversible and thus proceeds under kinetic control. Other soft carbon nucleophiles are anions from nitromethane, enolates, and enamines. 

Deprotonation of the ketone must be fast, complete, and irreversible for kinetic control of enolate formation. No equilibration of the enolates can be allowed to occur. Optimum conditions for kinetic control of deprotonation are Add the ketone slowly to an excess of very strong base (usually i-Pr2NLi, the anion of diisopropyl amine, p iabH = 36) in an aprotic solvent (such as dry tetrahydrofuran or dimethoxyethane). Since the A"eq for deprotonation of a ketone with this base is 10 = lO -, the reaction is... 

However, a A H calculation usually predicts the C-reacted compound to be thermodynamically more stable than the Z-reacted compound (mainly because of the greater C-Z bond strength in the C-reacted product compared to the C=C in the Z-reacted). However, this does depend on the relative C-E vs. 0-E bond strength. It is important to determine which is the dominant effect, product formation based upon product thermodynamic stability or upon kinetic direction from HSAB theory. To do this we need to determine whether the reaction is under kinetic or thermodynamic control. Figure 9.1 gives a flowchart for the decision for a common ambident nucleophile, an enolate anion (Z equals oxygen). 

The idea of kinetic versus thermodynamic control can be illustrated by discussing briefly the formation of enolate anions from unsymmetrical ketones. A more complete discussion of this topic is given in Chapter 7 and in Part B, Chapter 1. Any ketone with more than one type of a-proton can give rise to at least two enolates when a proton is abstracted. Many studies, particularly those of House,have shown that the ratio of the two possible enolates depends on the reaction conditions. If the base is very strong, such as the triphenylmethyl anion, and there are no hydroxylic solvents present, enolate 6 is the major product. When equilibrium is established between 5 and 6 by making enolate formation reversible by using a hydroxylic solvent, however, the dominant enolate is 5. Thus, 6 is the product of kinetic control... 

What does all of this mean The reaction of 2-pentanone with LDA in THF at -78°C constitutes typical kinetic control conditions. Therefore, formation of the kinetic enolate and subsequent reaction with benzaldehyde to give 34 is predictable based on the kinetic versus thermodynamic control arguments. In various experiments, the reaction with an unsymmetrical ketone under what are termed thermodynamic conditions leads to products derived from the more substituted (thermodynamic) enolate anion. Thermodynamic control conditions typically use a base such as sodium methoxide or sodium amide in an alcohol solvent at reflux. The yields of this reaction are not always good, as when 2-butanone (37) reacts with NaOEt in ethanol for 1 day. Self-condensation at the more substituted carbon occurs to give the dehydrated aldol product 38 in 14% yield. Note that the second step uses aqueous acid and, under these conditions, elimination of water occurs. 

In a reaction under kinetic control, the composition of the product mixture is determined by the relative rates of formation of each product. No equilibrium among possible alternative structures is set up. In the case of formation of enolate anions, kinetic control refers to the relative rates of removal of the alternative a-hydrogens. The less hindered a-hydrogen is removed more rapidly thus, the major product is the less substituted enolate anion. Because a slight excess of base is used, there is no ketone to serve as a proton donor and the less stable enolate anion cannot equilibrate with a more stable one. 

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. 

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