15.5:
Regioselective Formation of Enolates
Recall that the α-hydrogen atoms of carbonyl compounds are weakly acidic. When deprotonated by a base, they generate resonance-stabilized enolate ions.
Unsymmetrical ketones bearing nonequivalent α-hydrogen atoms yield two possible intermediates–less substituted or more substituted enolates.
As deprotonation is easier for a less-hindered proton, less-substituted enolates are formed comparatively faster. These are known as kinetic enolates. Because the more-substituted enolates bear a highly substituted double bond, they are more stable, and often known as thermodynamic enolates. Thus, thermodynamic enolates are at lower energy levels than kinetic enolates.
As the energy required to form thermodynamic enolates is higher, its formation requires a longer reaction time.
Regioselective formation of the enolates is possible depending on the reaction conditions.
To generate kinetic enolates, bulky non-nucleophilic strong bases in aprotic solvents are used to specifically abstract unhindered protons. In addition, maintaining a low reaction temperature forbids the equilibration of the two enolates.
As opposed, nonsterically hindered bases in protic solvents at room temperature favors formation of the thermodynamic enolate.
15.5:
Regioselective Formation of Enolates
As depicted in the figure below, the unsymmetrical ketones can form two possible enolates: less substituted or more substituted enolates. Usually, the thermodynamic enolates are formed from the more substituted α-carbon atom, while the kinetic enolates are formed faster by deprotonation from the less substituted position. The thermodynamic enolates have lower energy, so they are more stable. But the energy required to form kinetic enolates is less.
This regioselectivity in enolate formation is essentially an acid-base reaction and is controlled by various factors such as solvent, base, cation, and temperature. Protic solvents and weaker bases favor the formation of thermodynamic enolates, while aprotic solvents and stronger bases favor the kinetic enolates. Thermodynamic enolates are formed at higher temperatures and have longer reaction times because of the higher energy barrier. On the other hand, kinetic enolates are formed at lower temperatures with short reaction times. The conditions favoring thermodynamic enolates encourage a reversible reaction which is not the case with conditions involved for kinetic enolates intermediate.