• Note that although the carbonyl group is reactive toward nucleophiles at the carbonyl carbon, it is typically not reactive toward electrophiles, except at oxygen (not carbon). In contrast, the isomeric enol is reactive toward electrophiles at carbon.

• The Carbonyl group is much more thermodynamically stable than the alkene group, a factor which tends to cause the canonical structure having the carbonyl group to be lower in energy than the structure having the alkene group.
• The canonical structure which has the carbonyl group, however, has carbanion character, which tends to make it of higher energy than the structure which has the alkene function, because the latter has alkoxide character.
• These two opposing factors tend to cancel, making both structures nearly equal in energy.
• The existence of two nearly equal energy canonical structures maximizes resonance stabilization.

• Of course, the overall reaction is one which starts with the aldehyde or ketone and reacts this with bromine to give the alpha bromoaldehyde or ketone. The first stage of the reaction, the formation of the enol, is rate determining,i.e., the reaction of the enol with bromine is very fast. As a consequence, the reaction of an aldehyde or ketone with chlorine or iodine or other electrophiles occurs at exactly the same rate as bromination. The rate of enol formation is exactly equal to the rate of the overall reaction.
• The enolate is even more reactive as a nucleophile than the enol, and can react not only with strong electrophiles, but even with much weaker ones, like alkyl halides, to give alkylation at the alpha position.

In Acidic Solution, Enol Formation is Rate Determining! The subsequent reaction of the enol with bromine is very fast, so that the enol is prevented from returning to the keto form.

Details of the Mechanism of Acid Catalyzed Bromination of Carbonyl Compounds.

Mechanism of Base Promoted Bromination of Carbonyl Compounds.

THE ALDOL ADDITION REACTION.

The overall reaction and its mechanism are illustrated for the simplest aldehyde which undergoes the reaction, ethanal (acetaldehyde). [Incidentally, why does methanal note undergo the reaction?] The special importance of the reaction is that it forms a new C-C bond. It does this, in basic solution,by using the enolate as a nucleophile which adds to the electrophilic carbonyl carbon. The slow step is the addition to the carbonyl group, as usual. The product is both an aldehyde and an alcohol (-ol), therefore it was called an "aldol". The IUPAC name in this particular case is 3-hydroxybutanal.Incidentally, the reaction also proceeds in acidic solution, using the enol as the nucleophile and the conjugate acid of the aldehyde as a stronger electrophile.

Mechanism of the aldol addition:

RELATIVE REACTIVITIES OF THE ENOLATE, ENOL, AND A SIMPLE ALKENE. Recall that even simple alkenes are relatively nucleophilic (they react with electrophiles via the pi bond). The enol is more so because the -OH substituent donates electrons to the pi bond (see resonance structures for the enol, above). In other words, the enol has some carbanion character at the carbon beta to the hydroxyl group. The enolate, being negatively charged , is even more nucleophilic than the enol (please see scheme 18.7). In terms of resonance structures, the second resonance structure of the enol has charge separation and is a relatively minor contributor. In the enolate, neither structure has charge separation and both structures are relatively close together in energy. One structure has the stronger C=O bond, but the other has negative charge on oxygen rather than carbon.

THE ALDOL ADDITION MORE GENERALLY. It is important to note that an unbranched aldehyde, even a simple one like propanal, gives a branched aldol, because the enolate or enol always is formed at the alpha position to the carbonyl group. The branching therefore occurs alpha to the aldehyde functional group, not alpha to the hydroxyl group of the aldol. You should be able to predict the structure of an aldol product from any aldehyde or ketone. As you would expect, the aldol reaction works better with aldehydes than with ketones, because the equilibrium is less favorable for ketones (recall the greater thermodynamic stability of the ketone carbonyl). We will see how this problem can be resolved.

THE ALDOL CONDENSATION REACTION. The somewhat greater difficulty with which ketones are converted to their corresponding aldol products can be partially circumvented by carrying out the reaction as an aldol condensation reaction. In this reaction, in which the conditions are essentially the same as for the aldol addition, except that the reaction is warmed to RT or above, the initially formed aldol product is dehydrated to give an alpha,beta unsaturated carbonyl compound.

Mechanism of the Aldol Condensation

• The thermodynamic driving force for the reaction is supplied by the resonance stabilization of the unsaturated carbonyl function. The alkene pi bond is in conjugation with the carbonyl group, and the result is a pi electron system which is delocalized over four atoms, with the resulting resonance stabilization.
• The mechanism of the elimination reaction is somewhat unusuall, in that a hydroxide anion is eliminated as the leaving group from the enolate. Recall, that although it is not a good leaving group, hydroxide anion is a fairly stable anion. The things which favor its functioning as a leaving group in this reaction are: (1)There is a unit negative charge already in the molecule which provides a strong driving force and (2)the reactioni is intramolecular (favorable entropy). Both of theses are in contrast to simple SN2 reactions which are intermolecular and there is no negative charge in the alkyl halide.
• Notice that this elimination is stepwise, the base first abstracting the beta proton to give an enolate, followed by loss of the leaving hydroxide anion. In contrast, most beta eliminations are concerted. The reason this one is not is the ability to form a stable enolate intermediate.
• The reaction is called a condensation reaction because a small molecule (water) is eliminated.

RESONANCE STRUCTURES FOR THE ENONE

THE INTRAMOLECULAR ALDOL CONDENSATION. If two carbonyl groups are present in the same molecule, the aldol condensation can be carried out intramolecularly, one carbonyl group providing the source of the enolate and the other providing the carbonyl function. In most cases only the more stable 5 and 6 memebered rings are formed. See the Scheme below for one example.

Sketch of the Intramolecular aldol mechanism:

• Notice that the enolate could have been formed by removing a proton from the methyl group, but in this case addition to the other carbonyl group would have given a 7 membered ring. Verify this by showing the formation and ring closure of this enolate.

THE CROSSED ALDOL REACTION.

For a reaction of broader scope, it would be nice to be able to use two different carbonyl compounds in the aldol, since two different roles (enolate and carbonyl) are involved. However, if one does this in the most naieve way, as shown below, four different compounds can result, and generally will if both compounds have the ability to fulfill both roles. The Four Products from a crossed aldol reaction between ethanal and propanal

• However, some carbonyl compounds lack alpha hydrogens, and thus cannot form an enolate or enol. They can therefore only play the role of the carbonyl function. In such cases, crossed aldol reactions can be successful, as shown below.

There are two requirements for this procedure to be effective:

• One of the carbonyl compounds must lack an alpha type hydrogen and therefore not be able to supply an enolate component. There will therefore be only one possible enolate.
• The component which does have an alpha type hydrogen must be added last, gradually, so that a large excess of the non-enolizable carbonyl component is maintained. The reason for this is that the enolate can still add to either carbonyl component, giving two different aldols. If an excess of the non-enolizable component is maintained, the enolate will have a greater chance to add to this latter component to give the crossed aldol product, as opposed to the normal un-crossed aldol reaction of the enolizable carbonyl component.
• In the examples given, an excess of benzaldehyde or methanal would be maintained, and the enolizable component added last and gradually.

THE DIRECTED ALDOL REACTION: A MORE GENERAL SOLUTION TO THE PROBLEMS OF THE NARROW SCOPE OF THE CROSSED ALDOL REACTION IS THE DIRECTED ALDOL.

• This strategy involves the formation of the desired enolate in a separate step using the strong base LDA (lithium diisopropyl amide) which is able to convert the aldehyde or ketone quantitatively to its enol. Only then is the carbonyl component added. Note than different R groups can be used in the amide, but R= isopropyl is most often used. This gives a hindered amide which, unlike the simplest amide anion, does not tend to add to the carbonyl group as a nucleophile, but rather acts exclusively las a base.