Enolate ions aldol

Both of these problems are avoided by using a stronger base, such as LDA. With a stronger base, the ketone is irreversibly and quantitatively deprotonated to form enolate ions. Aldol reactions do not readily occur, because the ketone is no longer present. Also, the use of one equivalent of LDA ensures that none of the base survives after the enolate is formed. 

The point was made earlier (Section 5 9) that alcohols require acid catalysis in order to undergo dehydration to alkenes Thus it may seem strange that aldol addition products can be dehydrated in base This is another example of the way in which the enhanced acidity of protons at the a carbon atom affects the reactions of carbonyl com pounds Elimination may take place in a concerted E2 fashion or it may be stepwise and proceed through an enolate ion... 

In practice this reaction is difficult to carry out with simple aldehydes and ketones because aldol condensation competes with alkylation Furthermore it is not always possi ble to limit the reaction to the introduction of a single alkyl group The most successful alkylation procedures use p diketones as starting materials Because they are relatively acidic p diketones can be converted quantitatively to their enolate ions by weak bases and do not self condense Ideally the alkyl halide should be a methyl or primary alkyl halide... 

In the presence of strong bases, carbonyl compounds form enolate ions, which may be employed as nucleophilic reagents to attack alkyl halides or other suitably electron-deficient substrates giving carbon-carbon bonds. (The aldol and Claisen condensations... 

Aldol reactions, Like all carbonyl condensations, occur by nucleophilic addition of the enolate ion of the donor molecule to the carbonyl group of the acceptor molecule. The resultant tetrahedral intermediate is then protonated to give an alcohol product (Figure 23.2). The reverse process occurs in exactty the opposite manner base abstracts the -OH hydrogen from the aldol to yield a /3-keto alkoxide ion, which cleaves to give one molecule of enolate ion and one molecule of neutral carbonyl compound. 

On the other hand, carbonyl condensation reactions require only a catalytic amount of a relatively weak base rather than a full equivalent so that a small amount of enolate ion is generated in the presence of unreacted carbonyl compound. Once a condensation has occurred, the basic catalyst is regenerated. To carry out an aldol reaction on propanal, for instance, we might dissolve the aldehyde in methanol, add 0.05 equivalent of sodium methoxide, and then warm the mixture to give the aldol product. 

I If one of the carbonyl partners contains no or hydrogens, and thus can t form an enolate ion to become a donor, but does contain an unhindered carbonyl group and so is a good acceptor of nucleophiles, then a mixed aldol reaction is likely to be successful. This is the case, for instance, when either benz-aldehyde or formaldehyde is used as one of the carbonyl partners. 

G If one of the carbonyl partners is much more acidic than the other and so is transformed into its enolate ion in preference to the other, then a mixed aldol reaction is likely to be successful. Ethyl acetoacetate, for instance, is completely converted into its enolate ion in preference to enolate ion formation from monocarbonyl partners. Thus, aldol condensations of monoketones with ethyl acetoacetate occur preferentially to give the mixed product. 

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. 

The mixed Claisen condensation of two different esters is similar to the mixed aldol condensation of two different aldehydes or ketones (Section 23.5). Mixed Claisen reactions are successful only when one of the two ester components has no a hydrogens and thus can t form an enolate ion. For example, ethyl benzoate and ethyl formate can t form enolate ions and thus can t serve as donors. They can, however, act as the electrophilic acceptor components in reactions with other ester anions to give mixed /3-keto ester products. 

The first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a jS-keto ester or /3-diketone effects a conjugate addition to an a-,/3-unsaturated ketone, yielding a 1,5-diketone. But as we saw in Section 23.6,1,5-diketones undergo intramolecular aldol condensation to yield cyclohexenones when treated with base. Thus, the final product contains a six-membered ring, and an annulation has been accomplished. An example occurs during the commercial synthesis of the steroid hormone estrone (figure 23.9). 

In this example, the /3-diketone 2-methyJ-l,3-cyclopentanedione is used to generate the enolate ion required for Michael reaction and an aryl-substituted a,/3-unsaturated ketone is used as the acceptor. Base-catalyzed Michael reaction between the two partners yields an intermediate triketone, which then cyclizes in an intramolecular aldol condensation to give a Robinson annulation product. Several further transformations are required to complete the synthesis of estrone. 

Aldol reactions occur in many biological pathways, but are particularly important in carbohydrate metabolism, where enzymes called aldolases catalyze the addition of a ketone enolate ion to an aldehvde. Aldolases occur in all organisms and are of two types. Type 1 aldolases occur primarily in animals and higher plants type II aldolases occur primarily in fungi and bacteria. Both types catalyze the same kind of reaction, but type 1 aldolases operate place through an enamine, while type II aldolases require a metal ion (usually 7n2+) as Lewis acid and operate through an enolate ion. 

Step 2 of Figure 27.7 Aldol Condensation Acetoacetyl CoA next undergoes an aldol-like addition (Section 23.1) of an acetyl CoA enolate ion in a reaction catalyzed by 3-hydroxy-3-methylglutaryl-CoA synthase. The reaction again occurs... 

The enolate ion adds in an aldol-like reaction to a C=0 bond of carbon dioxide, yielding malonyl CoA. 

Step 2 of Figure 29.13 Decarboxylation and Phosphorylation Decarboxylation of oxaloacetate, a jB-keto acid, occurs by the typical retro-aldol mechanism like that in step 3 in the citric acid cycle (Figure 29.12), and phosphorylation of the resultant pyruvate enolate ion by GTP occurs concurrently to give phosphoenol-pyruvate. The reaction is catalyzed by phosphoenolpyruvate carboxykinase. 

In the aldol reaction the a carbon of one aldehyde or ketone molecule adds to the carbonyl carbon of another. Although acid catalyzed aldol reactions are known, the most common form of the reaction uses a base. The base most often used is OH, though stronger bases such as alkoxides (RO ) are sometimes employed. Hydroxide ion is not a strong enough base to convert substantially all of an aldehyde or ketone molecule to the corresponding enolate ion, that is, the equilibrium lies... 

An aldol reaction/condensation occurs when the enolate ion from an aldehyde or ketone attacks a molecule of the parent compound. If, however, two different carbonyl compounds are present, a crossed aldol reaction/ condensation occurs. 

Figure 2 shows illustrated mechanism for acetone self-condensation over calcined hydrotalcites, where the enolate ion is formed in a first step followed by two possible kinetic pathways 1) In the first case the subtracted proton is attracted by the basic sites and transferred to the oxygen of the enolate ion to form an enol in equilibrium. 2) In the second case the enolate ion reacts with an acetone molecule in the carbonyl group, to produce the aldol (diacetone alcohol). Finally, the p carbon is deprotonated to form a ternary carbon and then loses an OH group to obtain the final products. 

In general, any molecule capable of producing an enolate ion and also possessing two ligands for chelation of a metal ion will exhibit such a catalysis. For example, it has been reported (47) that magnesium ion catalyzes the aldol condensation of pyruvate with acetaldehyde, presumably through a mechanism such as ... 

Aldol reactions are often used to close five- and six-membered rings. Because of the favorable entropy (p. 211), such ring closures generally take place with ease, even where a ketone condenses with a ketone. An important example is the Robinson annulation reaction which has often been used in the synthesis of steroids and terpenes. In this reaction a cyclic ketone is converted to another cyclic ketone, with one additional six-membered ring containing a double bond. The substrate is treated with methyl vinyl ketone (or a simple derivative of methyl vinyl ketone) and a base.551 The enolate ion of the substrate adds to the methyl vinyl ketone in a Michael reaction (5-17) to give a diketone that undergoes or... 

From this we can conclude that two pKa values can be as much as eight units apart and AG will still be less than 50 kj / mol, low enough to permit rapid enzymatic reactions. However, for transfer of a proton from a C-H bond to a catalytic group, for example, to form an enolate ion for an aldol condensation (Chapter 13), the intrinsic barrier is known to be about 50 kj / mol.141 In this case, to allow rapid enzymatic reaction either the thermodynamic barrier must be very low, as a result of closely matching pKa values, or the enzyme must lower the intrinsic barrier. It may do both. 

B Ambident Nature of Enolate Ions in Aldol Addition... 

However, there are a number of complicating factors to consider. First, the basic conditions needed to form the enolate ions often lead to side reactions such as aldol addition and E2 elimination of RX compounds. Aldol addition is minimized if the carbonyl compound is a ketone with a structure unfavorable for aldol addition or if all of the carbonyl compound is converted to its enolate. To convert all of a simple carbonyl compound to its enolate usually requires a very strong base, such as NH2 in an aprotic solvent or liquid ammonia. Because the enolate anion itself is a strong base, best results are obtained when the halide, RX, does not undergo E2 reactions readily. 

In particular the synthesis of an a-alkylaldehyde or branched chain ketone by this overall strategy is of considerable merit since some of the problems associated with the a-alkylation of an enolate ion are largely avoided (e.g. competing aldol condensation in the case of an aldehyde, or polyalkylation and low regio-selective alkylation in the case of a ketone). 

In the aldol condensation, an enolate anion acts as a carbon nucleophile and adds to a carbonyl group to form a new carbon-carbon bond. Thus, the a-carbon of one aldehyde molecule becomes bonded to the carbonyl carbon of another aldehyde molecule to form an aldol (a 3-hydroxyaldehyde). In the mixed aldol condensation, the reactant with an a-hydrogen supplies the enolate anion, and the other reactant, usually without an a-hydrogen, supplies the carbonyl group to which the enolate ion adds. The aldol reaction is used commercially and also occurs in nature. 

The Claisen reaction involves the condensation or linking of two ester molecules to form a 3-ketoester (Fig.T). This reaction can be considered as the ester equivalent of the Aldol reaction The reaction involves the formation of an enolate ion from one ester molecule which then undergoes nucleophilic substitution with a second ester molecule (Fig.U, Step 1). 

Another nucleophilic addition involving a charged nucleophile is the Aldol reaction. This involves the nucleophilic addition of enolate ions to aldehydes and ketones to form p-hydroxycarbonyl compounds ... 

Enolate ions are formed by treating aldehydes or ketones with a base. An a-proton must be present. Enolate ions can undergo a number of important reactions including alkylation and the Aldol reactions. 

The mechanism of dehydration is shown below (Fig.L). First of all, the acidic proton is removed and a new enolate ion is formed. The electrons in the enolate ion can then move in such a fashion that the hydroxyl group is expelled to give the final product, i.e. an a, p-unsaturated aldehyde. In this example, it is possible to change the conditions such that one gets the Aldol reaction product or the a, P-unsaturated aldehyde, but in some cases only the a, p-unsaturated carbonyl product is obtained, particularly when extended conjugation is possible. 

This reaction proceeds well because the benzaldehyde has no a-protons and cannot form an enolate ion. Therefore, there is no chance of benzaldehyde undergoing self-condensation. It can only act as the electrophile for another enolate ion. However, what is to stop the ethanal undergoing an Aldol addition with itself as already described. 

In the photostimulated reaction of substrates with two leaving groups in 0-position, such as 0-dibromobenzene and acetone enolate ion, a disubstitution product (330) is formed. In the basic reaction conditions it leads, by an aldol condensation, to a final mixture of two acetylmethyl indenes 331a and 331b in 64% yield (equation 196)342. 

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