12.21:
Aldehydes and Ketones with Amines: Enamine Formation Mechanism
Enamine formation is an acid-catalyzed reversible reaction with two parts to its mechanism: The formation of carbinolamine and its subsequent conversion to enamine.
Carbinolamine formation begins with the nucleophilic attack of the amine to form a dipolar intermediate.
The mildly acidic ammonium ion protonates the negatively charged oxygen atom, followed by deprotonation of the nitrogen atom to give the carbinolamine.
Next, the hydroxyl group is converted into water such that a subsequent loss of the water molecule forms the iminium ion.
Finally, deprotonating the α hydrogen forms a new C=C π bond with the subsequent transfer of the C=N π electrons to nitrogen to generate the enamine.
Both enamine and imine formation mechanisms are identical, involving three key reaction types: Nucleophilic attack, proton transfer, and loss of leaving group.
The last step, however, is different. Abstracting the N–H proton gives an imine, while abstracting the C–H proton gives an enamine.
12.21:
Aldehydes and Ketones with Amines: Enamine Formation Mechanism
Enamine formation involves the addition of carbonyl compounds to a secondary amine through a series of reactions. The mechanism begins with the generation of carbinolamine, a nucleophilic attack followed by several proton transfer reactions. The hydroxyl group of the carbinolamine is converted into water to make a better leaving group that can push the reaction forward by eliminating a water molecule. In enamine formation, the last step involves the abstraction of a proton from the α carbon to form a C=C bond in the enamine. This differs from the last step of imine formation, where the N–H proton was abstracted to give the imine.
Enamines are formed under mildly acidic conditions. A pH of 4.5 is ideal for the reaction.
If the pH is low or the solution is too acidic, the reaction slows down in the first step—when the lone pair on the nitrogen atom of the amine attacks the carbonyl carbon of the substrate. A low pH indicates a high concentration of the protonated form of amine. The protonated amine cannot function as a nucleophile, slowing down this step’s rate.
If the pH is high or the solution is too basic, the fourth step of the reaction mechanism is affected. This is when the hydroxyl group of the carbinolamine is protonated to generate the leaving group, water. Highly basic conditions inhibit the process of water elimination by making the protonated amine, the proton donor in this step, less available for the reaction.
