So far the carbonyl group has been something nucleophiles attack. This chapter turns it around: a carbonyl makes the hydrogens next to it acidic enough to remove, and the anion that results is a carbon nucleophile. That single fact is what allows carbonyl compounds to react with each other, and it is the basis of most carbon–carbon bond formation in biology.
The alpha carbon and its unusually acidic hydrogens
The carbon directly attached to a carbonyl carbon is the alpha carbon, and hydrogens on it are alpha hydrogens. A ketone's alpha C–H has a pKa around 20 — dramatically more acidic than a plain alkane C–H at 50, and more acidic even than a terminal alkyne at 25.
Why: delocalization into the carbonyl
Removing an alpha hydrogen leaves a carbanion immediately adjacent to a carbonyl, and that lone pair delocalizes directly into the carbonyl pi system. The resulting anion is an enolate, and it has two resonance contributors: one with the charge on carbon, and one with the charge on oxygen and a C=C where the C–C was. The oxygen-centered form is the major contributor, since oxygen holds negative charge far better than carbon.
That split personality is the whole point of the enolate. Most of the charge sits on oxygen, which is what makes the anion stable enough to form — but the carbon-centered contributor is what makes it react at carbon. Stability from one contributor, reactivity from the other.
Two carbonyls do it again
If an alpha hydrogen sits between two carbonyls, the resulting anion delocalizes into both, and the acidity increases enormously.
| Compound | Alpha pKa |
|---|---|
| alkane | ~50 |
| ester | ~25 |
| ketone / aldehyde | ~19–20 |
| β-ketoester | ~11 |
| 1,3-diketone | ~9 |
A 1,3-diketone at pKa 9 is about as acidic as phenol and more acidic than ammonium — from a hydrogen on carbon. This is why 1,3-dicarbonyls are the workhorse nucleophiles of synthesis: an ordinary alkoxide deprotonates them completely, with no special reagents required.
Note also that an ester's alpha hydrogen (pKa 25) is markedly less acidic than a ketone's (20), because the ester's alkoxy oxygen is already donating into the carbonyl and there is less demand left for the alpha carbon to satisfy.
Choosing a base: two regimes
With a base whose pKaH is below the substrate's — hydroxide or ethoxide, around 16, against a ketone at 20 — deprotonation is incomplete, and you get a small equilibrium concentration of enolate coexisting with a large excess of unreacted ketone. That is exactly what an aldol reaction needs, since the ketone must be available as the electrophile.
With a base whose pKaH is well above the substrate's — LDA at about 36 — deprotonation is complete and irreversible. LDA is chosen because it is strong enough to do this and bulky enough not to attack the carbonyl carbon itself, which a small strong base would.
This also gives control over which enolate forms in an unsymmetrical ketone. LDA at −78 °C removes the most accessible proton fastest, giving the kinetic enolate, the less substituted one. A weaker base at higher temperature allows equilibration to the more stable, more substituted thermodynamic enolate. Same ketone, two different nucleophiles, chosen by conditions — the kinetic-versus-thermodynamic control idea in its clearest form.
The enol tautomer
Because the enolate's charge is shared between carbon and oxygen, it can be reprotonated at either. Protonating at carbon regenerates the ketone; protonating at oxygen gives the enol — a C=C bearing an OH, the same species that appeared fleetingly in alkyne hydration in Module 7.
Keto and enol are tautomers: constitutional isomers that interconvert rapidly, with a hydrogen genuinely in a different place. They are not resonance structures, and the distinction matters — draw them with ⇌, never ↔.
For a simple ketone the keto form dominates by roughly 10⁶ to one, because a C=O is much stronger than a C=C. But for a 1,3-diketone the enol can dominate: pentane-2,4-dione is about 80% enol in the pure liquid, because its enol is conjugated with the second carbonyl and internally hydrogen-bonded. Phenol is the extreme case — its "enol" form is aromatic, so it exists entirely as the enol and never as a ketone.
What enolates do
Once you have an enolate, the alpha carbon behaves like any carbon nucleophile. It does SN2 on an alkyl halide (alkylation, best with the doubly stabilized 1,3-dicarbonyls, since an ordinary enolate tends to do other things). It attacks aldehydes and ketones (the aldol reaction, next section). It attacks esters by acyl substitution (the Claisen condensation, the section after). And it reacts with halogens at the alpha position.
One consequence is worth noticing on its own: a stereocenter at an alpha carbon is destroyed by enolate formation, because the enolate is planar. Any chiral alpha carbon racemizes in the presence of acid or base, which is a real practical concern with chiral drugs and with amino acids.
What carries forward
The enolate is the nucleophile for the rest of this chapter. Kinetic versus thermodynamic control returns wherever two products compete under different conditions. And the fact that a 1,3-dicarbonyl is acidic enough for an ordinary base makes the acetoacetic ester and malonic ester syntheses possible — the classical routes to substituted ketones and carboxylic acids.