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Organic Chemistry Unit 7: Carbonyl chemistry

Carbonyl compounds react through nucleophilic addition, nucleophilic acyl substitution and enolate chemistry, forming new carbon–carbon bonds.

Covers: Aldehydes and ketones: nucleophilic addition, acetals, imines and the Wittig reaction, carboxylic acids and derivatives, nucleophilic acyl substitution, enolates and aldol reactions, Claisen condensation

Study guide

The carbonyl carbon is electrophilic because oxygen pulls electron density away. Aldehydes and ketones undergo nucleophilic addition: a nucleophile adds to the carbonyl carbon, forming a tetrahedral intermediate. Aldehydes are more reactive than ketones because they're less hindered and less stabilized by alkyl groups. Hydride reagents (NaBH₄, LiAlH₄) reduce them to alcohols, and Grignard reagents add carbon groups to form new C–C bonds. With alcohols and acid, aldehydes and ketones form acetals, which serve as protecting groups. With primary amines they form imines, and with secondary amines they form enamines. The Wittig reaction converts a carbonyl into an alkene using a phosphorus ylide.

Carboxylic acid derivatives undergo nucleophilic acyl substitution: a nucleophile adds, forming a tetrahedral intermediate, and a leaving group departs, keeping the carbonyl. Reactivity runs acid chlorides > anhydrides > esters ≈ carboxylic acids > amides, based on leaving group ability and resonance stabilization; more reactive derivatives can be converted into less reactive ones. Fischer esterification forms esters from carboxylic acids and alcohols with an acid catalyst. Esters hydrolyze in base (saponification) to carboxylate salts. LiAlH₄ reduces esters to primary alcohols and amides to amines, and nitriles can be hydrolyzed to carboxylic acids.

The α-hydrogens next to a carbonyl are acidic (pKa about 19–20 for ketones) because the resulting enolate is resonance-stabilized. Keto–enol tautomerism interconverts carbonyls and enols. Strong, bulky bases like LDA form enolates completely, at the less substituted α-carbon (kinetic enolate). Enolates are nucleophiles: they undergo α-halogenation and alkylation with alkyl halides. In the aldol reaction, an enolate adds to another carbonyl to form a β-hydroxy carbonyl, which can dehydrate to an α,β-unsaturated carbonyl (aldol condensation). The Claisen condensation joins two esters to form a β-keto ester. Michael additions add nucleophiles to α,β-unsaturated carbonyls in a conjugate fashion.

Monosaccharides are polyhydroxy aldehydes (aldoses) or ketones (ketoses). D or L is set by the OH on the stereocenter farthest from the carbonyl in a Fischer projection: right is D, left is L. In water, sugars cyclize into hemiacetals, as six-membered pyranoses or five-membered furanoses. This creates a new stereocenter, the anomeric carbon, with α and β anomers that interconvert (mutarotation). A sugar's hemiacetal OH reacts with an alcohol and acid to form a glycoside, which is an acetal. Disaccharides such as maltose and sucrose are joined by glycosidic bonds, named by anomer and carbon numbers (for example, α-1,4). Acid hydrolysis breaks these bonds back into monosaccharides.

Amines are nucleophiles that can be alkylated all the way to quaternary ammonium salts. In Hofmann elimination, exhaustive methylation with CH₃I and then heating with Ag₂O gives mainly the less substituted alkene. Reductive amination, an aldehyde or ketone plus an amine with NaBH₃CN, is a cleaner way to make amines. Water adds reversibly to aldehydes and ketones to form hydrates (gem-diols). Formaldehyde and aldehydes with electron-withdrawing groups are mostly hydrated at equilibrium, while most ketones stay mostly as the carbonyl because their alkyl groups add steric bulk and stabilize the carbonyl.

A hydrogen between two carbonyls is unusually acidic (pKa about 9–13), because the enolate is delocalized over both oxygens. 1,3-Dicarbonyls also have high enol content. In the malonic ester synthesis, diethyl malonate is deprotonated (NaOEt), alkylated with an alkyl halide, then hydrolyzed and heated, which removes CO₂ (decarboxylation) to give a substituted acetic acid. The acetoacetic ester synthesis works the same way to make methyl ketones. Grignard and organolithium reagents add directly to the carbonyl carbon (1,2-addition), and they add twice to esters and acid chlorides to give tertiary alcohols. They are destroyed by water, alcohols and acids, so they need dry conditions. Gilman reagents (R₂CuLi) instead do conjugate (1,4-) addition to α,β-unsaturated carbonyls, and they convert acid chlorides to ketones.

Esters are named as alkyl alkanoates (for example, ethyl ethanoate). Amides end in -amide, with N-substituents labeled N-. Nitriles end in -nitrile, and the nitrile carbon counts as C1. When a molecule has both a ketone and an aldehyde, the aldehyde is the suffix (-al) and the ketone becomes an oxo- prefix.

Key ideas

• The carbonyl carbon is electrophilic.
• Aldehydes and ketones undergo nucleophilic addition; aldehydes are more reactive.
• Acid derivatives undergo nucleophilic acyl substitution.
• Derivative reactivity: acid chloride > anhydride > ester > amide.
• Enolates form new C–C bonds through aldol and Claisen reactions.

Formulas and rules

Common mistakes

• Thinking NaBH₄ reduces esters readily; LiAlH₄ is needed.
• Forgetting that nucleophilic acyl substitution keeps the C=O, while addition to ketones doesn't.

Words to know

Carbonyl carbon

The electrophilic carbon of a C=O group.

Nucleophilic addition

A nucleophile adds to a carbonyl, forming a tetrahedral product.

Tetrahedral intermediate

The sp³ intermediate formed when a nucleophile attacks a carbonyl.

Acetal

A carbon bonded to two OR groups, used as a protecting group.

Imine

A C=N compound formed from a carbonyl and a primary amine.

Enamine

A compound formed from a carbonyl and a secondary amine.

Wittig reaction

Converts a carbonyl into an alkene using a phosphorus ylide.

Nucleophilic acyl substitution

Substitution at a carbonyl that keeps the C=O.

Acid chloride

The most reactive carboxylic acid derivative.

Fischer esterification

Making an ester from an acid and alcohol with acid catalyst.

Saponification

Base hydrolysis of an ester.

α-carbon

The carbon next to a carbonyl group.

Enolate

The resonance-stabilized anion formed by removing an α-hydrogen.

Tautomerism

Rapid interconversion of keto and enol forms.

LDA

A strong, bulky base that forms kinetic enolates.

Aldol reaction

An enolate adding to a carbonyl to form a β-hydroxy carbonyl.

Aldol condensation

An aldol reaction followed by dehydration.

Claisen condensation

Two esters combining to form a β-keto ester.

Michael addition

Conjugate addition to an α,β-unsaturated carbonyl.

Sample practice questions

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