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Organic Chemistry 2 Unit 7: Enols, Enolates and Alpha Substitution

Hydrogens on the carbon next to a carbonyl are unusually acidic, so carbonyl compounds form enols and enolates that act as carbon nucleophiles, letting chemists replace α-hydrogens with halogens, alkyl groups and more.

Covers: Keto-enol tautomerism, Acidity of α-hydrogens, Enolate formation: LDA, kinetic and thermodynamic enolates, α-Halogenation and the haloform reaction, Alkylation of enolates, Malonic ester and acetoacetic ester syntheses, Racemization and deuterium exchange

Study guide

A carbonyl compound with an α-hydrogen exists in equilibrium with its enol tautomer, in which the H has moved to oxygen and the C=O has become a C=C–OH. Tautomers are constitutional isomers, not resonance structures, because an atom actually moves. For simple ketones and aldehydes the keto form dominates heavily, since a C=O bond is stronger than a C=C bond. Enols become important when they are stabilized by conjugation and intramolecular hydrogen bonding, as in 2,4-pentanedione, which is mostly enol in nonpolar solvents, or by aromaticity, as in phenol. Tautomerization is catalyzed by acid (protonate O, then remove α-H) and by base (remove α-H, then protonate O). Because the enol and enolate are planar at the α-carbon, an α-stereocenter racemizes in acid or base, and α-hydrogens exchange for deuterium in D₂O with a trace of NaOD.

α-Hydrogens are acidic because the conjugate base, the enolate ion, is resonance-stabilized with negative charge shared between the α-carbon and the more electronegative oxygen. Typical pKa values are about 17 for aldehydes, 19 to 20 for ketones, 25 for esters and 25 for nitriles, while hydrogens between two carbonyls are far more acidic: about 9 for 2,4-pentanedione, 11 for ethyl acetoacetate and 13 for diethyl malonate. Whether a base forms the enolate completely depends on the pKa of its conjugate acid: K = 10^(pKa of conjugate acid of base − pKa of the carbonyl compound). Ethoxide (ethanol pKa 16) forms only a little ketone enolate but fully deprotonates a 1,3-dicarbonyl. Lithium diisopropylamide (LDA; diisopropylamine pKa about 36) is a strong, bulky, non-nucleophilic base that converts ketones and esters completely to enolates.

Unsymmetrical ketones can form two enolates. The kinetic enolate forms faster by removing the more accessible proton on the less substituted α-carbon; it is favored by LDA at −78 °C in THF, where deprotonation is fast and irreversible. The thermodynamic enolate has the more substituted C=C and is more stable; it is favored by weaker bases, protic solvents, higher temperatures or longer times, which allow equilibration. Enolates are good nucleophiles that react with methyl, primary, allylic and benzylic halides in SN2 reactions to form new C–C bonds at the α-carbon. Secondary halides react poorly and tertiary halides undergo E2. Using hydroxide or alkoxide to alkylate simple ketones gives mixtures, because the small enolate concentration allows aldol reactions and direct SN2 by the base.

α-Halogenation shows how acid and base differ. In acid, Br₂, Cl₂ or I₂ reacts with the enol; the rate law, rate = k[ketone][H⁺], is independent of halogen, because enol formation is rate-determining. One halogen is added cleanly, because the halogen makes the carbonyl oxygen less basic and slows further enol formation. In base, each halogen makes the remaining α-hydrogens more acidic, so halogenation repeats until the carbon is fully halogenated. With methyl ketones and excess halogen in base, the CX₃ group becomes a leaving group, giving a carboxylate and haloform (CHX₃): this is the haloform reaction, and the yellow precipitate of CHI₃ with I₂/NaOH is a test for methyl ketones. Carboxylic acids are α-brominated by the Hell-Volhard-Zelinsky reaction (Br₂ and PBr₃, then H₂O).

The malonic ester and acetoacetic ester syntheses use easily formed, stabilized enolates. Diethyl malonate is deprotonated by NaOEt, alkylated once or twice with alkyl halides, then hydrolyzed and heated with aqueous acid. The resulting malonic acid (a 1,3-diacid) loses CO₂ through a cyclic six-membered transition state, giving a substituted acetic acid, RCH₂COOH or RR'CHCOOH. Ethyl acetoacetate follows the same steps but gives a methyl ketone, CH₃COCH₂R or CH₃COCHRR'. Decarboxylation requires a carbonyl β to the COOH group, which accepts electrons to form an enol intermediate. Using a dihalide with two equivalents of base closes a ring; for example, malonic ester with 1,4-dibromobutane gives cyclopentanecarboxylic acid.

Key ideas

• Keto and enol forms are tautomers; the keto form dominates except when the enol is specially stabilized.
• α-Hydrogens are acidic because enolates are resonance-stabilized; 1,3-dicarbonyls are far more acidic.
• LDA forms enolates completely and gives the kinetic (less substituted) enolate at −78 °C.
• Enolates alkylate by SN2, so they need methyl, primary, allylic or benzylic halides.
• Acid-catalyzed halogenation stops at one halogen; base-promoted halogenation continues and gives the haloform reaction with methyl ketones.
• β-Keto acids and malonic acids decarboxylate on heating, the key step of malonic and acetoacetic syntheses.
• Enolization racemizes α-stereocenters and exchanges α-H for D.

Formulas and rules

Common mistakes

• Treating keto-enol tautomers as resonance structures.
• Using a tertiary alkyl halide in an enolate alkylation, where E2 wins.
• Swapping kinetic and thermodynamic enolates of an unsymmetrical ketone.
• Forgetting decarboxylation in malonic and acetoacetic ester syntheses, or losing the wrong carbon.
• Expecting monohalogenation of a methyl ketone in base instead of the haloform reaction.

Before the test, make sure you can

• Draw keto and enol tautomers and the acid- and base-catalyzed mechanisms connecting them.
• Rank α-hydrogen acidity and calculate deprotonation equilibrium constants from pKa values.
• Predict kinetic and thermodynamic enolates and their alkylation products.
• Predict acid- and base-promoted halogenation products, including the haloform reaction.
• Design malonic ester and acetoacetic ester syntheses of acids and methyl ketones.
• Explain why β-keto acids decarboxylate.
• Predict racemization and deuterium-exchange outcomes.

Words to know

α-Carbon

The carbon directly attached to a carbonyl carbon; its hydrogens are α-hydrogens.

Tautomers

Constitutional isomers that rapidly interconvert by moving a hydrogen and a double bond, such as keto and enol forms.

Enol

A tautomer with an OH on a C=C carbon, formed from an aldehyde or ketone.

Enolate ion

The resonance-stabilized anion formed by removing an α-hydrogen, nucleophilic at carbon.

LDA

Lithium diisopropylamide, a strong, bulky, non-nucleophilic base used to form enolates completely.

Kinetic enolate

The enolate formed fastest, usually at the less substituted α-carbon, favored by LDA at −78 °C.

Thermodynamic enolate

The more stable, more substituted enolate, favored under equilibrating conditions.

Haloform reaction

Base-promoted trihalogenation and cleavage of a methyl ketone to a carboxylate and CHX₃.

Iodoform test

Formation of yellow CHI₃ with I₂ and NaOH, indicating a methyl ketone or a CH₃CH(OH)– group.

Hell-Volhard-Zelinsky reaction

α-Bromination of a carboxylic acid using Br₂ and PBr₃, followed by water.

Malonic ester synthesis

Alkylation of diethyl malonate followed by hydrolysis and decarboxylation to make substituted acetic acids.

Acetoacetic ester synthesis

Alkylation of ethyl acetoacetate followed by hydrolysis and decarboxylation to make methyl ketones.

Decarboxylation

Loss of CO₂, which occurs readily on heating β-keto acids and 1,3-diacids through a cyclic transition state.

1,3-Dicarbonyl compound

A compound with two carbonyls separated by one carbon, whose central C–H is unusually acidic.

Racemization

Conversion of one enantiomer into a racemic mixture, as when an α-stereocenter enolizes.

Deuterium exchange

Replacement of α-H by D through repeated enolization in D₂O with acid or base.

Sample practice questions

30 more questions like these, from level 1 to 5, are in the practice set.