Chapter 23: Carbonyl Condensation Reactions
Two carbonyl partners, one new carbon-carbon bond
It is worth seeing at the outset that this chapter introduces no new mechanism. Alpha-substitution chemistry taught that a base removes an alpha proton to give an enolate, a nucleophile whose reactivity lives on carbon even though most of its charge lives on oxygen. That enolate then found an electrophile: an alkyl halide in a direct alkylation, a halogen molecule in a halogenation. A carbonyl condensation is the same opening move with a new electrophile — another carbonyl compound. The name says what happens: two molecules are joined into one, and in most of these reactions a small molecule…
The aldol reaction: a beta-hydroxy carbonyl compound
The mechanism has three steps and no surprises. Hydroxide removes an alpha proton from one molecule, giving the enolate; the enolate attacks the carbonyl carbon of a second molecule; the alkoxide product removes a proton from water to give the neutral alcohol and regenerate hydroxide. Base is a catalyst here, not a reagent consumed by the reaction, which is why a few mole percent suffices. With acetaldehyde the product is 3-hydroxybutanal — a molecule that is simultaneously an aldehyde and an alcohol, which is exactly where the name aldol comes from. Keep the two labels straight from the…
Dehydration: how an unfavorable equilibrium is pulled forward
The dehydration step converts a beta-hydroxy carbonyl compound into an alpha,beta-unsaturated carbonyl compound, and it is the step that earns the sequence its name: a reaction reported as an aldol condensation is one that has gone all the way to the enone, whereas an aldol reaction or aldol addition stops at the alcohol of the previous section. Placement matters and is easy to get wrong: the water molecule leaves as a hydroxide from the beta carbon and a proton from the alpha carbon, so the new double bond appears between the alpha and beta carbons and is therefore conjugated with the…
Mixed aldols: making two partners give one product
Begin by seeing clearly why the naive mixed aldol fails. Two different aldehydes or ketones, both with alpha hydrogens, are stirred with base. Each is deprotonated to some extent, so both enolates are present; each unreacted molecule is a potential acceptor, so both carbonyls are targets. That is two donors times two acceptors: four aldol products. Two are self-condensations and two are crossed. They usually have similar polarities and boiling points, so separating them is miserable, and each is formed in modest yield. As a rule, do not plan a synthesis around a mixed aldol unless you have…
Intramolecular aldol: rings from dicarbonyl compounds
An intramolecular reaction has an entropic advantage over the corresponding intermolecular one: the two reacting groups are already tethered, so they need not find each other in solution. When a dilute solution of a diketone meets base, ring closure therefore dominates over polymerization, provided the ring being formed is a comfortable size. Work through hexane-2,5-dione carefully once. Number the six carbons, so the ketones are at carbons two and five and the methyl groups are carbons one and six. Base removes a proton from carbon one, giving an enolate whose nucleophilic carbon is carbon…
The Claisen condensation: the acceptor has a leaving group
Set the Claisen beside the aldol and the whole chapter organizes itself. Both begin with a base removing an alpha proton to make an enolate, and both continue with that enolate attacking a carbonyl carbon. The two reactions diverge at the tetrahedral intermediate. When the acceptor was an aldehyde or a ketone, the intermediate alkoxide had only hydrogen and carbon substituents, nothing worth expelling, so it took a proton and the reaction ended as an addition. When the acceptor is an ester, the same intermediate carries an alkoxy group on the former carbonyl carbon. Alkoxide is a serviceable…
The Dieckmann cyclization: a Claisen that closes a ring
Nothing mechanistic is new here, so the value of the section is in prediction and in seeing the connection to earlier chemistry. Take diethyl hexanedioate and number its chain from one ester carbonyl carbon as carbon one to the other as carbon six. Ethoxide removes a proton from carbon two, which is alpha to the carbon-one ester. The enolate at carbon two attacks the carbonyl carbon at carbon six. The tetrahedral intermediate at carbon six expels ethoxide and reforms a carbonyl, so carbon six becomes a ketone. The new ring is bounded by the bond just made, and it encloses carbons two, three,…
The Michael reaction: attacking the far end of a conjugated acceptor
Start with the acceptor and why it has two electrophilic sites. In an alpha,beta-unsaturated carbonyl compound the alkene pi system and the carbonyl pi system are conjugated. Drawing the resonance forms makes the consequence explicit: alongside the usual form with positive character on the carbonyl carbon, there is a form with the negative charge on oxygen and the positive charge on the beta carbon. The beta carbon is therefore electrophilic too, and a nucleophile attacking there gives an enolate that is subsequently protonated on carbon. This overall outcome — nucleophile on the beta carbon,…
The Stork reaction: an enamine does an enolate's job without strong base
The problem the Stork reaction solves is worth stating precisely. Conjugate addition works best with stabilized, reversible nucleophiles, which in practice means doubly activated donors of pKa 9 to 13. A simple ketone at pKa 19 is not deprotonated to any useful extent by an alkoxide, and generating its enolate completely requires a strong, hindered base at low temperature — workable, but the resulting unstabilized enolate is reactive enough to give competing 1,2-addition and other side reactions. The enamine route sidesteps the whole difficulty by producing a nucleophile that needs no base at…
The Robinson annulation: the chapter's two big reactions in one flask
Annulation simply means ring building, and the Robinson annulation is a good place to end the chapter because it requires nothing new. Every step has appeared already; the achievement is in the combination, and in noticing that the product of one reaction is precisely the substrate the next one needs. Stage one, the Michael addition. A stabilized enolate adds to the beta carbon of an alpha,beta-unsaturated ketone. Both partners are chosen for the usual reasons: the donor is doubly activated, so a mild base deprotonates it completely and it is the only nucleophile in the flask, and the…
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