The Aldol Condensation

Thermodynamic Control. Treatment of a ketone with a weaker base, such as sodium hydroxide or alkoxide, in the presence of a protic solvent such as an alcohol provides an equilibrium mixture containing the ketone and its enolates. Of the two regioisomeric enolates, the more stable one, termed the thermodynamic enolate, is present in greater amounts. For 2-methylcyclohexanone, the thermodynamic enolate is the one with the more substituted double bond, resulting from a-proton abstraction at C-2. 

One of the important distinctions between kinetic and thermodynamic control of enolate formation is that conditions of kinetic control give rapid and complete enolate formation. Formation of the kinetic enolate is essentially irreversible under these conditions. The conditions of thermodynamic control establish an equilibrium containing both enolate and ketone. Some consequences of this distinction will be seen in later sections of this chapter. 

Write the structures of all possible enolates of each of the following ketones. Which is kinetically favored Thermodynamically favored  

We have just seen that treatment of most aldehydes and ketones (those having a hydrogens with a pA a of 16-20) with bases such as hydroxide and alkoxide gives a solution containing significant quantities of both the aldehyde or ketone and its enolate. Instead of simply maintaining an equilibrium between the carbonyl compound and its enolate, however, carbon-carbon bond formation can occur. 

The resulting equilibrium lies to the right for many aldehydes and to the left for most ketones. The (3-hydroxy aldehyde product is called an aldol because it contains both an aldehyde and an alcohol function aid + ol = aldol), and the carbon-carbon bond-forming reaction is referred to as aldol addition  

In the reversal of these equilibria, the enol then adds D at the a-carbon. 

Repetition of this sequence results in exchange of the other a-hydrogen. 

Enolate anions may act as carbon nucleophiles. They add reversibly to the carbonyl group of another aldehyde or ketone molecule in a reaction called the aldol condensation, an extremely useful carbon-carbon bond-forming reaction. 

The simplest example of an aldol condensation is the combination of two acetaldehyde molecules, which occurs when a solution of acetaldehyde is treated with catalytic amounts of aqueous base. 

An enolate anion adds to the carbonyl group of an aldehyde or ketone In an aldol condensation. An aldol is a 3-hydroxyaldehyde or 3-hydroxyketone. 

A major drawback of the reaction as originally formulated is self-condensation. The enolate derived from 3-pentanone (see 120) exists in an equilibrium with the ketone and benzaldehyde under these eonditions. 

Enolate 120 can react with benzaldehyde to give the aldolate product 121 and hydrolysis gives the alcohol. In this case, diastereomers are formed, 122 and 123 and, at this point, we cannot predict one or the other as a major product. For the time being, we will assume that the reaction produces close to a 1 1 mixture of the two products. If this mixture is heated, conjugated ketone 124 is formed. The problem with this approach is clear when we recognize that enolate 120 can also react with unenolized 3-pentanone to produce the selfcondensation aldol product (125) and hydrolysis provides 126. Therefore, this reaction could produce three different aldol products. 

There are certainly cases when we want a crossed-aldol condensation between two reactive partners that have an enolizable position, as in 3-pentanone with cyclopentanone. If 3-pentanone and benzaldehyde, which has no enolizable protons, can lead to three products, what will happen in this new case If an aldol condensation occurs under thermodynamic conditions. 3-pentanone reacts with sodium ethoxide to give enolate 120. This enolate can condense with either unenolized 3-pentanone (to produce 126) or with unenolized cyclopentanone (to produce 128). Both of these ketones are symmetrical, and there is no opportunity for additional enolates, which would further complicate the reaction (see below). The pAa of 3-pentanone and cyclopentanone are not 

If an unsymmetrical ketone is used in this reaction, the problem is exacerbated. Reaction of 42 with sodium ethoxide, under thermodynamic control conditions, generates two different enolate anions. When reacted with an aldehyde with no a-hydrogens (benzaldehyde), two aldol products are formed (131 and 132). When 42 reacts with sodium ethoxide under thermodynamic conditions in the presence of an unsymmetrical ketone such as 2-butanone, the kinetic and thermodynamic enolates of both ketones are formed, which means that four different enolate anions are formed, and each one reacts with two different ketones. Therefore, the attempted mixed aldol condensation of 2-butanone and 42, therefore, produces eight different aldol products. 

There are countless synthetic examples of the aldol condensation. In one example taken from Massanet s synthesis of eudesmanolides, diketone 134 was converted to the enolate anion with LDA. In a second step, methyl pyruvate was added to give a 98% yield of 135 and 136 in about a 1 1 ratio. 

You may have noticed that aldehydes were conspicuously absent from the examples of alkylation reactions presented in Sections 20.3 and 20.4. This is due to the high reactivity of the carbonyl carbon of an aldehyde as an electrophile. When an enolate anion nucleophile is generated from an aldehyde, under most circumstances it rapidly reacts with the electrophilic carbonyl carbon of an un-ionized aldehyde molecule. Although this reaction, known as the aldol condensation, interferes with the alkylation of aldehydes, it is a very useful synthetic reaction in its own right. The aldol condensation of ethanal is shown in the following equation  

The product, 3-hydroxybutanal, is also known as aldol and gives rise to the name for the whole class of reactions. 

O The base, hydroxide ion, removes an acidic hydrogen from the a-carbon of the aldehyde. The conjugate base of the aldehyde is a stronger base than hydroxide, so the equilibrium for this first step favors the reactants. 

However, enough enolate ion nucleophile is present to react with the electrophilic carbonyl carbon of a second aldehyde molecule. 

This part of the mechanism is just like the mechanism for the addition reactions of Chapter 18. The enolate nucleophile adds to the carbonyl carbon of a second aldehyde molecule, and the negative oxygen removes a proton from water. This step regenerates hydroxide ion, so the reaction is base catalyzed. 

As noted earlier, an aldehyde is partially converted to its enolate anion by bases such as hydroxide ion and alkoxide ions. 

In a solution that contains both an aldehyde and its enolate ion, the enolate undergoes nucleophilic addition to the carbonyl group. This addition is analogous to the addition reactions of other nucleophilic reagents to aldehydes and ketones described in Chapter 17. 

The alkoxide formed in the nucleophilic addition step then abstracts a proton from the solvent (usually water or ethanol) to yield the product of aldol addition. This product is known as an aldol because it contains both an aldehyde function and a hydroxyl group 

Carbonyl group to which This is the carbon—carbon 

Some of the earliest studies of the aldol reaction were carried out by Aleksander Borodin. Though a physician by training and a chemist by profession, Borodin is remembered as the composer of some of the most familiar works in Russian music. See pp. 326-327 in the April 1987 issue of the Journal of Chemical Education for a biographical sketch of Borodin. 

0 One of these protons is removed by base to form an enolate ( OH 0 

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Cannizzaro reaction Two molecules of many aldehydes, under the influence of dilute alkalis, will interact, so that one is reduced to the corresponding alcohol, while the other is oxidized to the acid. Benzaldehyde gives benzyl alcohol and benzoic acid. Compare the aldol condensation. 

When a mixture of aniline, hydrochloric acid and acetaldehyde is heated (in the absence of an oxidising agent), a vigorous reaction occurs with the pro duction of quinaldine. In these circumstances, the main reactions are undoubtedly, (i) the acetaldehyde undergoes the aldol condensation, and the... 

Apart from the thoroughly studied aqueous Diels-Alder reaction, a limited number of other transformations have been reported to benefit considerably from the use of water. These include the aldol condensation , the benzoin condensation , the Baylis-Hillman reaction (tertiary-amine catalysed coupling of aldehydes with acrylic acid derivatives) and pericyclic reactions like the 1,3-dipolar cycloaddition and the Qaisen rearrangement (see below). These reactions have one thing in common a negative volume of activation. This observation has tempted many authors to propose hydrophobic effects as primary cause of ftie observed rate enhancements. 

The higjily water-soluble dienophiles 2.4f and2.4g have been synthesised as outlined in Scheme 2.5. Both compounds were prepared from p-(bromomethyl)benzaldehyde (2.8) which was synthesised by reducing p-(bromomethyl)benzonitrile (2.7) with diisobutyl aluminium hydride following a literature procedure2.4f was obtained in two steps by conversion of 2.8 to the corresponding sodium sulfonate (2.9), followed by an aldol reaction with 2-acetylpyridine. In the preparation of 2.4g the sequence of steps had to be reversed Here, the aldol condensation of 2.8 with 2-acetylpyridine was followed by nucleophilic substitution of the bromide of 2.10 by trimethylamine. Attempts to prepare 2.4f from 2.10 by treatment with sodium sulfite failed, due to decomposition of 2.10 under the conditions required for the substitution by sulfite anion. 

Difunctional target molecules are generally easily disconnected in a re/ro-Michael type transform. As an example we have chosen a simple symmetrical molecule, namely 4-(4-methoxyphenyl)-2,6-heptanedione. Only p-anisaldehyde and two acetone equivalents are needed as starting materials. The antithesis scheme given helow is self-explanatory. The aldol condensation product must be synthesized first and then be reacted under controlled conditions with a second enolate (e.g. a silyl enolate plus TiCl4 or a lithium enolate), enamine (M. Pfau, 1979), or best with acetoacetic ester anion as acetone equivalents. 

A number of aldehydes and ketones are prepared both m industry and m the lab oratory by a reaction known as the aldol condensation which will be discussed m detail in Chapter 18... 

Write the structure of the aldol condensation product of eacfT... 

The carbon-carbon bond forming potential of the aldol condensation has been extended beyond the self condensations described in this section to cases in which two different carbonyl compounds react m what are called mixed aldol condensations... 

The base-catalyzed reaction of acetaldehyde with excess formaldehyde [50-00-0] is the commercial route to pentaerythritol [115-77-5]. The aldol condensation of three moles of formaldehyde with one mole of acetaldehyde is foUowed by a crossed Cannizzaro reaction between pentaerythrose, the intermediate product, and formaldehyde to give pentaerythritol (57). The process proceeds to completion without isolation of the intermediate. Pentaerythrose [3818-32-4] has also been made by condensing acetaldehyde and formaldehyde at 45°C using magnesium oxide as a catalyst (58). The vapor-phase reaction of acetaldehyde and formaldehyde at 475°C over a catalyst composed of lanthanum oxide on siHca gel gives acrolein [107-02-8] (59). 

Manufacture and Processing. 2,2,4-Trimethyl-l,3-pentanediol can be produced by hydrogenation of the aldehyde trimer resulting from the aldol condensation of isobutyraldehyde [78-84-2]. 

Early patents indicated that because water inhibits the aldol condensation mechanism, it was necessary to dry recycle acetone to less than 1% water (139—142). More recent reports demonstrate DAA production from waste acetone containing 10—50% water (143), and enhanced DAA production over anion-exchange resins using acetone feeds that contain 3—10% water (144,145). 

Methyl isoamyl ketone (MIAK), a product derived from the aldol condensation of isobutyraldehyde and acetone, is used principally as a solvent for lacquers, ceUulosics, and epoxies. 

Kelkar and McCarthy (1995) proposed another method to use the feedforward experiments to develop a kinetic model in a CSTR. An initial experimental design is augmented in a stepwise manner with additional experiments until a satisfactory model is developed. For augmenting data, experiments are selected in a way to increase the determinant of the correlation matrix. The method is demonstrated on kinetic model development for the aldol condensation of acetone over a mixed oxide catalyst. 

According to this concept, the aldol condensation normally occurs through a chairlike transition state. It is further assumed that the stmcture of this transition state is sufficiently similar to that of chair cyclohexane to allow the conformational concepts developed for cyclohexane derivatives to be applied. Thus, in the example above, the reacting aldehyde is shown with R rather than H in the equatorial-like position. The differences in stability of the various transition states, and therefore the product ratios, are governed by the steric interactions between substituents. 

It is also possible to carry out the aldol condensation under acidic conditions. The reactive nucleophile is then the enol. The mechanism, as established in detail for acetaldehyde, involves nucleophilic attack of the enol on the protonated aldehyde. 

In Robinson s now well-known suggestions, regarding the processes by which alkaloids may be produced in plants, two main reactions are used j the aldol condensation and the similar condensation of carbinol-amines, resulting from the combination of an aldehyde or ketone with ammonia or an amine, and containing the group. C(OH). N., with substances in which the group, CH. CO. is present. By these reactions it is possible to form the alkaloid skeleton, and the further necessary changes postulated include oxidations or reductions and elimination of water for the formation of an aromatic nucleus or of an ethylene derivative. 

The azlactones of a-benzoylaminocinnamic acids have traditionally been prepared by the action of hippuric acid (1, Ri = Ph) and acetic anhydride upon aromatic aldehydes, usually in the presence of sodium acetate. The formation of the oxazolone (2) in Erlenmeyer-Plochl synthesis is supported by good evidence. The method is a way to important intermediate products used in the synthesis of a-amino acids, peptides and related compounds. The aldol condensation reaction of azlactones (2) with carbonyl compounds is often followed by hydrolysis to provide unsaturated a-acylamino acid (4). Reduction yields the corresponding amino acid (6), while drastic hydrolysis gives the a-0X0 acid (5). ... 

The aldol condensation of phenylthiobutenone 304 with aldehydes in CH2CI2 via dienodibutylborinates 305 leads to the adduct 306 in 61% yield (diastereo-selectivity >97%) (90TL2213). 

The cyclization of 306 promoted by trimethylsilyl trifiate and diisopropylethyl-amine gives cw-dihydropyrones 307. Under these conditions methoxybutenone fails to form the aldol condensation product 305 (90TL2213). 

An alternative route for n-hutanol is through the aldol condensation of acetaldehyde (Chapter 7). 

Ethylhexanol is produced hy the aldol condensation of hutyralde-hyde. The reaction occurs in presence of aqueous caustic soda and produces 2-ethyl-3-hydroxyhexanal. The aldehyde is then dehydrated and hydrogenated to 2-ethylhexanol ... 

Tire mechanism of the Claisen condensation is similar to that of the aldol condensation and involves the nucleophilic addition of an ester enolate ion to the carbonyl group of a second ester molecule. The only difference between the aldol condensation of an aldeiwde or ketone and the Claisen condensation of an ester involves the fate of the initially formed tetrahedral intermediate. The tetrahedral intermediate in the aldol reaction is protonated to give an alcohol product—exactly the behavior previously seen for aldehydes and ketones (Section 19.4). The tetrahedral intermediate in the Claisen reaction, however, expels an alkoxide leaving group to yield an acyl substitution product—exactly the behavior previously seen for esters (Section 21.6). The mechanism of the Claisen condensation reaction is shown in Figure 23.5. 

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