Regiochemistry and Stereochemistry of Enolate Formation

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 

Any equilibrium will produce the thermodynamically most stable enolate. The most stable enolate will have the greatest charge delocalization. In the above example, the thermodynamically favored enolate is conjugated the kinetically favored enolate is not. Common conditions for thermodynamic control are to use average bases (like sodium ethoxide or potassium tert-butoxide, p abH 16 to 19) in alcohol solvents. Proton transfer equilibria rapidly occur among base, solvent, ketone, and enolate. Sodium hydride or potassium hydride in an ether solvent are also thermodynamic reaction conditions that allow equilibration between the ketone and the enolate. Enones have two possible enolates weaker bases give the thermodynamically more stable extended enolate, whereas kinetic conditions produce the cross-conjugated enolate. 

In addition to regiochemistry, acyclic carbonyl compounds can produce two possible stereoisomeric enolates, E or Z, as shown above. Steric interactions determine the favored enolate stereochemistry. Under reversible conditions, Z enolates are more stable than E as they minimize steric interactions, especially if R is large. Z enolates are also usually favored under irreversible conditions in polar aprotic solvents like HMPA that complex cations well and break up ion pairing, effectively reducing the bulk around the oxygen anion. Under irreversible conditions in ether solvents, the E enolate is often favored because the steric size of the base/cation aggregate around the oxygen dominates, especially if R is smaller, as with esters. 

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These deprotonations generate extended enoiates, which are vinylogous allylic sources. Deprotonation can also occur on the methyl next to the carbonyl in the following example. However, the extended enolate is more delocalized. Section 9.3 covers the regiochemistry and stereochemistry of enolate formation in more detail. 

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