MCAT Organic Chemistry Review

Aldehyde and Ketones II: Enolates

7.2 Enolate Chemistry

Due to the acidity of the α-hydrogen, aldehydes and ketones exist in solution as a mixture of two isomers: the familiar keto form, and the enol form.

KETO–ENOL TAUTOMERIZATION

The enol form gets its name from the presence of a carbon–carbon double bond (the en– component) and an alcohol (the –ol component). The two isomers, which differ in the placement of a proton and the double bond, are called tautomers. The equilibrium between the tautomers lies far to the keto side, so there will be many more keto isomers in solution. The process of interconverting from the keto to the enol tautomer, shown in Figure 7.2, is called enolization, or, more generally, tautomerization.

Figure 7.2. Enolization (Tautomerization) On the left is the keto form, which is thermodynamically favored over the enol form on the right.

KEY CONCEPT

Aldehydes and ketones exist in the traditional keto form (C=O) and as the less common enol tautomer (enol = ene + ol). The enol form can act as a nucleophile. Note that tautomers are not resonance structures because they have different connectivity of atoms.

Enols are important intermediates in many reactions of aldehydes and ketones. The enolate carbanion results from the deprotonation of the α-carbon by a strong base, as described earlier. Common strong bases include the hydroxide ion, lithium diisopropyl amide (LDA), and potassium hydride (KH). A 1,3-dicarbonyl is particularly acidic because there are two carbonyls to delocalize negative charge and, as such, is often used to form enolate carbanions. Once formed, the nucleophilic carbanion reacts readily with electrophiles. We will see one example of this shortly in the aldol condensation. Another example of this type of reaction is a Michael addition, shown in Figure 7.3, in which the carbanion attacks an α,β-unsaturated carbonyl compound—a molecule with a multiple bond between the α- and β-carbons next to a carbonyl.

Figure 7.3. Michael Addition (a) The base deprotonates the α-carbon, making it a good nucleophile; (b) The carbanion attacks the double bond, resulting in a Michael addition.

This reaction proceeds as shown due to the resonance stabilization of the intermediates. The better you understand the resonance forms of molecules, the more you will be able to predict the specific location on a molecule where a reaction will occur.

KINETIC AND THERMODYNAMIC ENOLATES

Given a ketone that has two different alkyl groups, each of which may have α-hydrogens, two forms of the enolate can form, with the carbon–carbon double bond between the carbonyl carbon and either the more or less substituted carbon, as shown in Figure 7.4. The equilibrium between these forms is dictated by the kinetic and thermodynamic control of the reaction. The kinetically controlled product is formed more rapidly but is less stable. This form has the double bond to the less substituted α-carbon. As expected, this product is formed by the removal of the α-hydrogen from the less substituted α-carbon. The thermodynamically controlled product is formed more slowly, but is more stable and features the double bond being formed with the more substituted α-carbon. Accordingly, this is formed by the removal of the α-hydrogen from the more substituted α-carbon.

Figure 7.4. Kinetic and Thermodynamic Enolates The kinetic enolate forms more quickly, but is less stable than the thermodynamic enolate.

Each of these two products is favored by different conditions. The kinetic product is favored in reactions that are rapid, irreversible, at lower temperatures, and with a strong, sterically hindered base. If the reaction is reversible, the kinetic product can revert to the original reactant and react again to form the thermodynamic product. The thermodynamic product is favored with higher temperatures; slow, reversible reactions; and weaker, smaller bases.

ENAMINES

Just as enols are tautomers of carbonyls, enamines are tautomers of imines. An imine is a compound that contains a C=N bond. The nitrogen in the imine may or may not be bound to an alkyl group or other substituent. Through tautomerization (movement of a hydrogen and a double bond), imines can be converted into enamines, as shown in Figure 7.5.

Figure 7.5. Enamination (Tautomerization) On the right is the imine form, which is thermodynamically favored over the enamine form on the left.

MCAT Concept Check 7.2:

Before you move on, assess your understanding of the material with these questions.

1.    What are tautomers?

2.    Which tautomer of aldehydes and ketones is thermodynamically favored: keto or enol?

3.    Which role does the enolate carbanion play in organic reactions: nucleophile, electrophile, oxidizing agent, or reducing agent?

4.    What conditions favor the kinetic enolate form? The thermodynamic enolate form?

·        Kinetic enolate:

·        Thermodynamic enolate: