Reactions of Enols and Enolates
Ketones and aldehydes are in equilibrium with a small amount of the corresponding
enol.
This can be problematic, if one desires to produce a stereogenic center a to a C=O.
But the enol form is also useful since the electron-rich double
bond can serve as a mild nucleophile toward reactive
electrophiles.
Alternatively, the proton on the a-carbon can be abstracted by a strong base to
generate a (resonance-stabilized) enolate anion.
This enolate anion is a much stronger nucleophile than the corresponding enol.
The Aldol Condensation
Reaction
Ketone Enolate + Aldehyde
Notice that, in this case, the product alcohol dehydrated
to form an a,b-unsaturated carbonyl as a product.
Intramolecular Aldol
Ester Enolate + Aldehyde
Ester Enolate + Ester =
Claisen Condensation
Intramolecular Claisen
Condensation = Dieckmann
Condensation
1,4-Conjugate Addition: The Michael
Reaction
(Notice that the presence of the conjugated C=C-C=O system is crucial, since this
both polarizes the C=C and also leads to a resonance-stabilized carbanion, after
addition of the nucleophile)
Conjugate additions are promoted by the addition of copper salts, which are believed
to function by coordination with the C=C, prior to addition of the nucleophile.
Decarboxylation
Reactions
Decarboxylation produce CO2, and are thus thermodynamically favorable.
These reactions proceed most readily when the COOH moiety is attached to an
electronegative atom, like oxygen or nitrogen.
Unstabilized Carbanion is
NOT formed
However, even in the case of simple carboxylic acid, decarboxylation may proceed
readily, if the resultant carbanion is stabilized by resonance, or other electronegative
substituent, as shown for acetoacetic acid below.
Stabilized (enolate) carbanion is
formed
The reaction probably proceeds through a cyclic transition state as shown below.
Notice that saponification of the ester moiety (followed by acidification) does not
produce the corresponding carboxylic acid, but instead the decarboxylated product.
(Note that the ketoester is stable, but the corresponding ketoacid is not.)
Carbamates are frequently used as ‘protecting groups’ for
amines.
Recall that tert-butyl esters are cleaved by strong acid, since the tertiary
carbocation is the most stable. In the example below, cleavage of the ester is
followed by decarboxylation.
The tert-butyloxycarbonyl group is often used as a protecting group for amines,
and is abbreviate Boc.
The commercially available reagent, di-tert-butyldicarbonate, (Boc2O), is used to
form the Boc-protected amine, which is then manipulated synthetically as desired,
and eventually cleaved with strong acid as shown above.
Recall that benzyl esters are cleaved by hydrogenolysis. Notice that, in the example
below, the ester is cleaved, followed by decarboxylation to produce the free amine.
(Notice that the tert-butyl ester and the ethyl carbamate are unaffected by these
conditions)
The carbobenzyloxycarbonyl protecting group, shown
previously, is abbreviated Cbz, or sometimes Z.
The Acetoacetic Ester Synthesis
The Acetoacetic Ester Synthesis uses an extra ethoxycarbonyl group to stabilize the
anion alpha to the ketone. Following alkylation of the (highly stabilized) enolate,
the carboethoxy group is removed by hydrolysis and decarboxylation.
The Malonic Ester Synthesis