06 Enols, Enolates, and Carbon–Carbon Bond Formation
Learn how carbonyl compounds form enols and enolates, and how enolates create carbon–carbon bonds in aldol, alkylation, Claisen, and Michael reactions.
From carbonyl compounds to enolates
The carbon next to a carbonyl carbon is the . A hydrogen attached to it is an alpha hydrogen. These hydrogens are more acidic than ordinary alkane hydrogens because removing one forms a resonance-stabilized species.
Two related products can form when an alpha proton is removed:
: A neutral structure with a hydroxyl group attached to a carbon–carbon double bond. Enolization can be acid- or base-catalyzed. Under acid catalysis, the carbonyl oxygen is protonated before an alpha proton is removed; under base catalysis, the steps occur in the opposite order.
: An anion whose negative charge is shared between oxygen and the through resonance. Its carbon end commonly forms new carbon–carbon bonds.
For acetone, the can be represented by these resonance contributors:
The contributors represent one resonance-stabilized species. The acts as a nucleophile: its carbon end can bond to an electrophilic carbon, while the carbonyl group is regenerated after protonation or other work-up.
Choosing between enolates
When a carbonyl compound has nonequivalent alpha positions, it may form more than one . The tends to form faster, often by removal of a more accessible alpha hydrogen. Rapid deprotonation with a strong, bulky base such as LDA in THF at low temperature often favors this outcome.
The is the more stable and often has the more substituted carbon–carbon double bond. Reversible enolization that allows equilibration often favors it. These are useful trends, not guarantees: substrate structure and reaction conditions affect the result.
To predict which forms, identify the alpha hydrogens that can be removed, then consider whether the conditions favor rapid, selective deprotonation or equilibration.
Aldol bond formation and dehydration
In an , an donor attacks the carbonyl carbon of an aldehyde or ketone acceptor. The new bond connects the donor’s to the acceptor’s carbonyl carbon. Protonation of the resulting alkoxide gives a beta-hydroxy carbonyl compound.
For example, two propanal molecules can react under dilute base to give 3-hydroxy-2-methylpentanal:
Base removes an alpha proton from one propanal molecule, forming an .
The ’s carbon end attacks the carbonyl carbon of a second propanal molecule, forming an alkoxide.
Proton transfer gives the beta-hydroxy aldehyde and regenerates the base.
Heating or other dehydration-promoting conditions can convert the addition product into a conjugated alpha,beta-unsaturated carbonyl. Under basic conditions, this commonly occurs by E1cB elimination: a proton is removed from the , followed by loss of the beta-hydroxyl group. The beta-hydroxy compound is the aldol addition product; its dehydrated product is often called the aldol condensation product.
A uses two different carbonyl compounds. If both can form enolates, several products may result. Selectivity can often be improved by using an acceptor with no alpha hydrogens, such as benzaldehyde, or by preforming one before adding the electrophile.
Other carbon–carbon bond reactions
Enolates also form carbon–carbon bonds through alkylation, , and conjugate addition. Distinguish these reactions by identifying the electrophile and the step that forms the new bond.
Alpha-alkylation: An reacts with an alkyl electrophile, commonly a primary alkyl halide, by substitution. The alkyl group replaces an alpha hydrogen. For example, forming the cyclohexanone with LDA and then adding methyl iodide gives 2-methylcyclohexanone. Primary electrophiles are generally most suitable; secondary and tertiary electrophiles are more prone to elimination or hindered substitution. Preforming the helps limit competing aldol reactions.
: An ester attacks another ester’s carbonyl carbon. The tetrahedral intermediate expels an alkoxide, yielding a beta-keto ester. Two molecules of ethyl acetate form ethyl acetoacetate after work-up. The base is typically chosen to match the ester’s alkoxy group; acidic work-up protonates the product.
: An adds to the beta carbon of an alpha,beta-unsaturated carbonyl compound. This conjugate, or 1,4-, addition forms a new bond at the donor’s . Stabilized enolates, such as those formed from beta-dicarbonyl compounds, are common donors.
A practical approach to product prediction
For any -based synthesis, identify the donor, which forms the , and the acceptor, which acts as the electrophile. Then track the two carbon atoms that form the new bond.
Choose conditions to control formation and limit competing reactions. Catalytic, reversible base conditions can promote aldol addition, while strong base and a preformed are commonly used for alpha-alkylation. Aldol reactions and Claisen condensations both build carbon–carbon bonds with donors, but a proceeds by nucleophilic acyl substitution and produces a beta-keto ester.
Takeaway: Identify the -forming partner, locate the electrophilic atom, and match the reaction conditions to the intended pathway.