Carbonyl chemistry · 9 min read

Carbonyl chemistry: addition, acyl substitution and enolates

A huge share of organic chemistry is the carbonyl group behaving in one of three ways. Learn these three patterns and dozens of named reactions fall into place.

Pattern 1: nucleophilic addition (aldehydes and ketones)

The C=O carbon is electrophilic. A nucleophile attacks it, the π electrons move onto oxygen, and a tetrahedral alkoxide forms. If nothing can leave, the alkoxide is protonated to give an alcohol. See the basic version in Hydride adds to acetaldehyde's carbonyl.

Hydride donors (NaBH₄, LiAlH₄) give alcohols: NaBH₄ reduction of a ketone, LiAlH₄ reduction of an ester to a primary alcohol.
Organometallics (RMgX, RLi) give new C–C bonds and alcohols: Grignard addition to acetaldehyde.
Cyanide gives cyanohydrins and underlies the Strecker synthesis.
Ylides convert C=O into C=C: Wittig reaction, HWE.
Amines add and then lose water to give imines: Schiff base formation.

Reactivity: aldehydes > ketones, because aldehydes have less steric hindrance and less electron donation from alkyl groups. Electron-withdrawing groups next to the carbonyl increase reactivity.

Pattern 2: addition–elimination (carboxylic acid derivatives)

Acid derivatives have a leaving group on the carbonyl carbon. The nucleophile adds to give a tetrahedral intermediate, then the C=O re-forms and the leaving group is expelled. The net result is substitution at the acyl carbon.

Reactivity order, most to least reactive: acid chloride > anhydride > thioester > ester ≈ carboxylic acid > amide > carboxylate. A more reactive derivative can always be converted into a less reactive one, but not the other way round without activation.

Esters and acids: Fischer esterification, ester hydrolysis, Base-catalyzed transesterification.
Amides: DCC coupling, amide hydrolysis, Schotten–Baumann acylation.
Acid chlorides and Grignards: Grignard + ester adds twice because the ketone formed is more reactive than the ester.

Acid or base catalysis helps in different ways. Acid protonates the carbonyl oxygen, making the carbon more electrophilic. Base generates a stronger nucleophile (an alkoxide instead of an alcohol).

Pattern 3: enolates and enols (the α-carbon is nucleophilic)

A hydrogen on the carbon next to a carbonyl is mildly acidic (pKa about 19–20 for ketones, about 25 for esters). Removing it gives an enolate, which is nucleophilic at carbon. The enolate then attacks an electrophile.

Attack on another carbonyl: Base-catalyzed aldol addition of acetaldehyde, Claisen condensation of ethyl acetate, Knoevenagel condensation, Mannich reaction.
Attack on a conjugated acceptor: Michael addition, leading to the Robinson annulation when followed by an aldol.
Attack on an alkyl halide: alkylation, an SN2 reaction in which the enolate is the nucleophile.
Attack on halogen: Haloform reaction of a methyl ketone.

Kinetic versus thermodynamic enolates

An unsymmetrical ketone can lose either α-hydrogen. A bulky strong base at low temperature (LDA, −78 °C) removes the more accessible, less substituted H quickly: the kinetic enolate. A weaker base at higher temperature, where proton transfer is reversible, gives the more substituted, more stable thermodynamic enolate. Choosing between them lets you alkylate on one side or the other.

How to tell which pattern you are in

Is there a leaving group on the carbonyl carbon? Yes: acyl substitution. No: addition.
Is the nucleophile the α-carbon of another carbonyl compound? Then you are in enolate chemistry.
Is the carbonyl conjugated to a C=C? Consider 1,4-addition (Michael) as well as 1,2-addition.

Hard, charge-dense nucleophiles (RLi, hydride) tend to add 1,2 to the carbonyl. Soft, stabilised nucleophiles (enolates, cuprates, thiolates) tend to add 1,4.

Practise in the interactive app Browse all 345 reactions