MCAT Organic Chemistry Review

Aldehyde and Ketones II: Enolates

Conclusion

In this second chapter on aldehydes and ketones, we’ve taken a look at the important resonance structures that the carbonyl of aldehydes and ketones allows. The high electronegativity of the oxygen atom in a carbonyl not only makes the carbonyl carbon electrophilic, but also weakens the C–H bonds on α-carbons. Deprotonation of this α-carbon results in an enolate, a nucleophilic version of carbonyl-containing compounds. Thus, while the carbonyl carbon dictates the electrophilic chemistry of carbonyls, it is the α-carbon, along with its acidic hydrogens, that dictates the nucleophilic chemistry of carbonyls.

Aldehydes and ketones are not the only carbonyl-containing compounds, of course. Carboxylic acids and their derivatives, including esters, anhydrides, and amides, also have chemistry controlled by a carbonyl. But there is one critical difference between aldehydes and ketones, and carboxylic acids and their derivatives: the absence or presence of a leaving group. While aldehydes and ketones lack leaving groups, carboxylic acids and carboxylic acid derivatives have leaving groups with varying degrees of stability. Over the next two chapters, we’ll explore the chemistry of these interesting groups of compounds.

Concept Summary

General Principles

·        The carbon adjacent to the carbonyl carbon is termed an α-carbon; the hydrogens attached to the α-carbon are called α-hydrogens.

·        α-Hydrogens are relatively acidic and can be removed by a strong base.

o   The electron-withdrawing oxygen of the carbonyl weakens the C–H bonds on α-carbons.

o   The enolate resulting from deprotonation can be stabilized by resonance with the carbonyl.

·        Ketones are less reactive toward nucleophiles because of steric hindrance and α-carbanion destabilization.

o   The presence of an additional alkyl group crowds the transition step and increases its energy.

o   The alkyl group also donates electron density to the carbanion, making it less stable.

Enolate Chemistry

·        Aldehydes and ketones exist in the traditional keto form (C=O) and in the less common enol form (enol = ene + ol = double bond + alcohol).

o   Tautomers are isomers that can be interconverted by moving a hydrogen and a double bond. The keto and enol forms are tautomers of each other.

o   The enol form can be deprotonated as an enolate. Enolates are good nucleophiles.

·        In the Michael addition, an enolate attacks an α,β-unsaturated carbonyl, creating a bond.

·        The kinetic enolate is favored by fast, irreversible reactions at lower temperatures with strong, sterically hindered bases. The thermodynamic enolate is favored by slower, reversible reactions at higher temperatures with weaker, smaller bases.

·        Enamines are tautomers of imines. Like enols, enamines are the less common tautomer.

Aldol Condensation

·        In the aldol condensation, the aldehyde or ketone acts as both nucleophile and electrophile, resulting in the formation of a carbon–carbon bond in a new molecule called an aldol.

o   An aldol contains both aldehyde and alcohol functional groups.

o   The nucleophile is the enolate formed from the deprotonation of the α-carbon.

o   The electrophile is the aldehyde or ketone in the form of the keto tautomer.

o   First, a condensation reaction occurs in which the two molecules come together.

o   After the aldol is formed, a dehydration reaction (loss of a water molecule) occurs. This results in an α,β-unsaturated carbonyl.

·        Retro-aldol reactions are the reverse of aldol condensations.

o   Retro-aldol reactions are catalyzed by heat and base.

o   In these reactions, the bond between an α- and β-carbon is cleaved.

Answers to Concept Checks

·        7.1

1.    The α-hydrogens of aldehydes and ketones are acidic, or deprotonate easily, due to both inductive effects and resonance effects. The electronegative oxygen atom pulls electron density from the C–H bond, weakening it. Once deprotonated, the resonance stabilization of the negative charge between the α-carbon, carbonyl carbon, and electrophilic carbonyl oxygen increases the stability of this form.

2.    The α-hydrogens of aldehydes are slightly more acidic due to the electron-donating characteristics of the second alkyl group in ketones. This extra alkyl group destabilizes the carbanion, which slightly disfavors the loss of the α-hydrogens in ketones as compared to aldehydes.

3.    Steric hindrance is one of the two reasons that aldehydes are slightly more reactive than ketones. The additional alkyl group gets in the way and makes for a higher-energy intermediate.

·        7.2

1.    Tautomers are isomers that can be interconverted by the movement of a hydrogen and a double bond.

2.    The keto form is thermodynamically favored.

3.    Enolate carbanions act as nucleophiles.

4.    Because the kinetic enolate forms rapidly and can interconvert with the thermodynamic form if given time, the kinetic form is favored by fast, irreversible reactions, such as with a strong, sterically hindered base, and lower temperatures. The thermodynamic form, on the other hand, is favored by slower, reversible reactions, with weaker or smaller bases, and higher temperatures.

·        7.3

1.    The enol or enolate carbanion acts as the nucleophile (the deprotonated aldehyde or ketone).

2.    The keto form of the aldehyde or ketone acts as the electrophile.

3.    A retro-aldol reaction is the reverse of an aldol reaction and can be favored by the addition of base and heat. In this reaction, a bond between the α-and β-carbons of a carbonyl is broken.

4.    An aldol condensation is a condensation reaction, in which two molecules are joined to form a single molecule with the loss of a small molecule; a dehydration reaction, in which a molecule of water is lost; and a nucleophile–electrophile reaction, in which a nucleophile pushes an electron pair to form a bond with an electrophile.

Shared Concepts

·        General Chemistry Chapter 5

o   Chemical Kinetics

·        Organic Chemistry Chapter 4

o   Analyzing Organic Reactions

·        Organic Chemistry Chapter 6

o   Aldehydes and Ketones I

·        Organic Chemistry Chapter 8

o   Carboxylic Acids

·        Organic Chemistry Chapter 9

o   Carboxylic Acid Derivatives

·        Organic Chemistry Chapter 10

o   Nitrogen- and Phosphorus-Containing Compounds