Aldol and Claisen Condensations

 Chapter -21

Carbanions I Aldol and Claisen Condensations

Acidity of a-hydrogens

• In our introduction to aldehydes and ketones, we learned that it is the carbonyl group that largely determines the chemistry of aldehydes and ketones. At that time, we saw in part how the carbonyl group does this: by providing a site at which nucleophilic addition can take place. Now we are ready to learn another part of the story: how the carbonyl group strengthens the acidity of the hydrogen atoms attached to the a-carbon and, by doing this, gives rise to a whole set of chemical reactions.

• resonance that is possible only through participation by the carbonyl group. Resonance of this kind is not possible for carbanions formed by ionization of ^-hydrogens, y-hydrogens, etc., from saturated carbonyl compounds.

• We shall use the term carbanion to describe ions like I since part of the charge is carried by carbon, even though the stability that gives these ions their importance is due to the very fact that most of the charge is not carried by carbon but by We saw before that the susceptibility of the carbonyl group to nucleophilic attack is due to the ability of oxygen to accommodate the negative charge that develops as a result of the

 Reactions involving carbanions

• The carbonyl group occurs in compounds other than aldehydes and ketones in esters, for example and, wherever it is, it makes any a-hydrogens acidic and thus aids information of carbanions. Since these a-hydrogens are only weakly acidic, however, the carbanions are highly basic, exceedingly reactive particles. In their reactions they behave as we would expect as nucleophiles. As nucleophiles, carbanions can attack carbon and, in doing so, form carbon-carbon bonds. From the standpoint of synthesis, acid-strengthening by carbonyl groups is probably the most important structural effect in organic chemistry.

• We shall take up first the behavior of ketones toward the halogens and see evidence that carbanions do indeed exist; at the sometime, we shall see an elegant example of the application of kinetics, stereochemistry, and isotopic tracers to the understanding of reaction mechanisms. And while we are at it, we shall see something of the role that keto-enol tautomerism plays in the chemistry of carbonyl compounds.

• Next, we shall turn to reactions in which the carbonyl group plays both its roles: the aldol condensation, in which a carbanion generated from one molecule of aldehyde or ketone adds, as a nucleophile, to the carbonyl group of a second molecule; and the Claisen condensation, in which a carbanion generated from one molecule of ester attacks the carbonyl group of a second molecule, with acyl substitution as the final result.

Base-promoted halogenation of ketone

• Acetone reacts with bromine to form bromoacetone; the reaction is accelerated by bases (e.g., hydroxide ion, acetate ion, etc.). Study of the kinetics shows that

• slowly abstracts a proton (step 1) from acetone to form carbanion, which then reacts rapidly with bromine (step 2) to yield bromoacetone. Step (1), generation of the carbanion. is the rate-determining step, since its rate determines the overall rate of the reaction sequence. As fast as carbanions are generated, they are snapped up by bromine molecules.

• Strong support for this interpretation comes from the kinetics of iodination. Here, too, the rate of reaction depends upon, [acetone] and [: B] but is independent of [I 2 ], Furthermore, and most significant, at a given [acetone] and [: B], bromination and iodination proceed at identical rates. That is to say, in the rate expresses.

Acid-catalyzed halogenation of ketones. Enolization

• Acids, like bases, speed up the halogenation of ketones. Acids are not, however, consumed, and hence we may properly speak of acid-catalyzed halogenation (as contrasted to base-promoted halogenation). Although the reaction is not,

• strictly speaking, a part of carbanion chemistry, this is perhaps the best place to take it up, since it shows a striking parallel in every aspect to the base-promoted reaction we have just left.

• Here, too, the kinetics show the rate of halogenation to be independent of halogen concentration, but dependent upon ketone concentration and, this time, acid concentration. Here, too, we find the remarkable identity of rate constants for apparently different reactions: fpr bromination and iodination of acetone, and exchange of its hydrogens for deuterium; for iodination and racemization of phenyl 1 sec-butyl ketone. 

• The ion formed in this case, I, is an exceedingly stable one, owing its stability to the fact that it is hardly a "carbonium" ion at all, since oxygen can carry the charge and still have an octet of electrons. The ion is, actually, a protonated ketone; loss of the proton yields the product, bromoacetone.

Aldol condensation

• Under the influence of dilute base or dilute acid, two molecules of an aldehyde or a ketone may combine to form a 0-hydroxyaldehyde or 0-hydroxyketone. This reaction is called the Akol condensation. In every case the product results from addition of one molecule of aldehyde (or ketone) to a second molecule in such a way" that the a-carbon of the first becomes attached to the carbonyl carbon of the second. For example:

• The carbonyl group plays two roles in the aldol condensation. It not only provides the unsaturated linkage at which addition (step 2) occurs, but also makes the a-hydrogens acidic enough for carbanion formation (step 1) to take place.

Dehydration of aldol products

• he jff-hydroxyaldehydes and jiff-hydroxyketones obtained from aldol condensations are very easily dehydrated; the major products have the carbon-carbon double bond between the a- and 0-carbon atoms. For example:

• As we know, an alkene in which the carbon-carbon double bond is conjugated with an aromatic ring is particularly stable in those cases where elimination of water from the aldol product can form such a conjugated alkene, the unsaturated aldehyde or ketone is the product actually isolated from the reaction. For example:

Use of aldol condensation in synthesis

• Catalytic hydrogenation of, j8-unsaturated aldehydes and ketones yields saturated alcohols, addition of hydrogen occurring both at carbon-carbon and at carbon-oxygen double bonds. It is for the purpose of ultimately preparing saturated alcohols that the aldol condensation is often carried out. For example, /i-butyl alcohol and 2-ethyl-l-hexanol are both prepared on an industrial scale in this way:

• mixture of the four possible products may be obtained. On a commercial scale, however, such a synthesis may be worthwhile if the mixture can be separated, and the components marketed.

Reactions related to the aldol condensation

• There are a large number of condensations that are closely related to the aldol condensation. Each of these reactions has its own name Perkin, Knoevenagel, Doepner, Claisen, Dieckmann, for example and at first glance each may seem quite different from the others. Closer examination shows, however, that like the aldol condensation each of these involves attack by a carbanion on a carbonyl group. In each case the carbanion is generated in very much the same way: the abstraction by base of a hydrogen ion alpha to a carbonyl group. Different bases may be used sodium hydroxide, sodium ethoxide, sodium acetate, amines and the carbonyl group to which the hydrogen is alpha may vary aldehyde, ketone, anhydride, ester but the chemistry is essentially the same as that of the aldol condensation. We shall take up a few of these condensations in the following problems and in following sections; in doing this, we must not lose sight of the fundamental resemblance of each of them to the aldol condensation.

The Wittig reaction

• In 1954, Georg Wittig (then at the University of Tübingen) reported a method of synthesizing alkenes from carbonyl compounds, which amounts to the replace- 

• The reaction is carried out under mild conditions, and the position of the carbon-carbon double bond is not in doubt. Carbonyl compounds may contain a wide variety of substituents, and so may the ylide. (Indeed, in its broadest form, the Wittig reaction involves reactants other than carbonyl compounds, and may lead to products other than substituted alkenes.)

• (a) How do your account for formation of II? (b) What product would you expect from the action of sodium ethoxide on ethyl pixelated (ethyl heptamerization)? (c) Would you expect similar behavior from ethyl glutamates or ethyl succinate? Actually, ethyl succinate reacts with sodium ethoxide to yield a compound of formula CiCi 2 H leftie containing a six-membered ring. What is the likely structure for this last product?

Crossed Claisen condensation

• Like a crossed aldol condensation, a crossed Claisen condensation is generally feasible only when one of the reactants has no a-hydrogens and thus is incapable of undergoing self-condensation. For example:

Reformats reaction. Preparation of /3-hydroxy esters

• In the Claisen condensation, we have just seen, carbanions are generated from esters through abstraction of an a-hydrogen by base. But we are familiar with another way of generating carbanions or rather, groups with considerable carbanion character: through formation of organometallic compounds. This approach, too, plays a part in the chemistry of esters. If an a-bromo ester is treated with metallic zinc in the presence of an aldehyde or ketone, there is obtained a j8-hydroxy ester. This reaction, known as the Reformat sky reaction, is the most important method of preparing 0-hydroxy acids and their derivatives. For example:

• The a-bromo ester and zinc react in absolute ether to yield an intermediate organozinc compound, which then adds to the carbonyl group of the aldehyde or ketone. The formation and subsequent reaction of the organozinc compound is similar to the formation and reaction of a Grignard reagent. Zinc is used in place of magnesium simply because the organozinc compounds are less reactive than Grignard reagents; they do not react with the ester function but only with the aldehyde or ketone.