Ketones aldol addition products

As with other reversible nucleophilic addition reactions the equilibria for aldol additions are less favorable for ketones than for aldehydes For example only 2% of the aldol addition product of acetone is present at equilibrium... 

Among the compounds capable of forming enolates, the alkylation of ketones has been most widely studied and applied synthetically. Similar reactions of esters, amides, and nitriles have also been developed. Alkylation of aldehyde enolates is not very common. One reason is that aldehydes are rapidly converted to aldol addition products by base. (See Chapter 2 for a discussion of this reaction.) Only when the enolate can be rapidly and quantitatively formed is aldol formation avoided. Success has been reported using potassium amide in liquid ammonia67 and potassium hydride in tetrahydrofuran.68 Alkylation via enamines or enamine anions provides a more general method for alkylation of aldehydes. These reactions are discussed in Section 1.3. 

The addition of an alkaline earth metal enolate A to a carbonyl compound is always an exer-gonic process irrespective of whether the enolate is derived from a ketone, an ester, or an amide and whether the carbonyl compound is an aldehyde or a ketone (Figure 13.44, top). One of the reasons for this exergonicity hes in the fact that the alkaline earth metal ion is part of a chelate in the alkoxide B of the aldol addition product. The driving forces for the additions of alkaline earth metal enolates of esters and amides to carbonyl compounds are further increased because the aldol adducts B are resonance-stabilized, whereas the enolates are not. 

The sodio derivative of methylpyrazine (20) reacts with aldehydes and ketones to give secondary and tertiary pyrazine carbinols, respectively.175, 178 Yields in the range 21-99% are obtained when the molar ratio of methylpyrazine sodamide carbonyl compound used is 2 2 1. Oppenauer oxidation of 1-phenyl-2-pyrazylethand (21), the aldol addition product of methylpyrazine and benzaldehyde, gives phenacylpyrazine (22) in 18% yield.176... 

This is one of the more complicated-looking syntheses that we have seen. First, analyze the product for the two Michael components. The carbon-carbon double bond arises from dehydration of the aldol addition product, and is located where one of the two C=0 groups of the original diketone used to be. The Michael addition takes place at the carbon between these ketone groups. The Michael acceptor is an enone that can also enter into the aldol condensation and furnishes the methyl group attached to the double bond. 

An aldol addition is a reaction between two molecules of an aldehyde or two molecules of a ketone. When the reactant is an aldehyde, the addition product is a jS-hydroxyaldehyde, which is why the reaction is called an aldol addition ( aid for aldehyde, ol for alcohol). When the reactant is a ketone, the addition product is a jS-hydroxyketone. Because the addition reaction is reversible, good yields of the addition product are obtained only if it is removed from the solution as it is formed. 

Section 19.12 Dehydration of Aldol Addition Products Formation of a,j8-Unsaturated Aldehydes and Ketones 807... 

As we shall see, the initial aldol addition product often dehydrates to form an a,/3-unsaturated aldehyde or ketone. When this is the result, the overall reaction is an aldol condensation. First let us consider the mechanism of an aldol addition. 

With ketones, the addition step leading to the aldol is unfavorable due to steric hindrance, and the equilibrium favors the aldol precursors rather than the addition product (Section 19.4B). However, as we shall see in Section 19.4C, dehydration of the aldol addition product can draw the equilibrium toward completion, whether the reactant is an aldehyde or a ketone. Enolate additions to both aldehydes and ketones are also feasible when a stronger base (such as LDA) is used in an aprotic solvent (Section 19.5B). 

This result is not surprising, because we know that the equilibrium for an aldol addition (the reverse of the reaction above) is not favorable when the enolate adds to a ketone. But, as mentioned earlier, dehydration of an aldol addition product can draw the equilibrium forward. We shall discuss the dehydration of aldols next (Section 19.4C). 

When each of the following ketones is treated with aqueous sodium hydroxide, the aldol product is obtained in poor yields. In these cases, special distillation techniques are used to increase the yield of aldol product. In each case, predict the aldol addition product that is obtained, and propose a mechanism for its formation ... 

When the reaction is performed at low temperature, the aldol addition product is obtained, but the yield is very poor. As explained earlier, the starting material is a ketone, and the equilibrium does not favor formation of the aldol addition product. However, when the reaction is performed at an elevated temperature, the aldol condensation product is obtained in very good yield, because the equilibrium is driven by formation of a conjugated it system. 

Dehydration of an aldol addition product leads to a conjugated a,/8-unsaturated carbonyl system. The overall process is called an aldol condensation, and the product can be called an enal (alkene a/dehyde) or enone (alkene ketone), depending on the carbonyl group in the product. The stability of the conjugated enal or enone system means that the dehydration equilibrium is essentially irreversible. For example, the aldol addition reaction that leads to 3-hydroxybutanal, shown in Section 19.4, dehydrates on heating to form 2-butenal. A mechanism for the dehydration is shown here. 

Because an aldol addition is reversible, when the product of an aldol addition (the jS-hydroxyaldehyde or 8-hydroxyketone) is heated with hydroxide ion and water, the aldehyde or ketone that formed the aldol addition product can be regenerated. In Section 18.21 we will see that a retro-aldol addition is an important reaction... 

The Dehydration of Aldol Addition Products Forms a,/3-Unsaturated Aldehydes and Ketones 871... 

THE DEHYDRATION OF ALDOL ADDITION PRODUCTS FORMS a,/3-UNSATURATED ALDEHYDES AND KETONES... 

C)5W=C(0Et)CH=C(0Et)CH=CR(02CR)]. Aldehydes or ketones react with the [diosphine complexes, [(OC)4(PR3)Cr=C(OMe)Me] to give aldol condensation products. Reaction with the amino carbene complexes [(OC)sCr=C(NMe2)Me] results in aldol addition products. Aldol reactions of optically active aminocarbene complexes proceed with moderate to high diastereoselectivity. Photolysis of chromium alkoxycaibene complexes with aldehydes in the presence of Lewis acids produces -lactones in low yield. Intramolecular reaction by incorporation of the aldehyde into either side chain of the carbene complex is considerably more efficient. ... 

Even though ketones have the potential to react with themselves by aldol addition recall that the position of equilibrium for such reactions lies to the side of the starting materials (Section 18 9) On the other hand acylation of ketone enolates gives products (p keto esters or p diketones) that are converted to stabilized anions under the reaction conditions Consequently ketone acylation is observed to the exclusion of aldol addition when ketones are treated with base m the presence of esters... 

Butyraldehyde undergoes stereoselective crossed aldol addition with diethyl ketone [96-22-0] ia the presence of a staimous triflate catalyst (14) to give a predominantiy erythro product (3). Other stereoselective crossed aldol reactions of //-butyraldehyde have been reported (15). 

Aldol condensation (Sections 18.9-18.10) When an aldol addition is carried out so that the (i-hydroxy aldehyde or ketone dehydrates under the conditions of its formation, the product is described as arising by an aldol condensation. 

The first element of stereocontrol in aldol addition reactions of ketone enolates is the enolate structure. Most enolates can exist as two stereoisomers. In Section 1.1.2, we discussed the factors that influence enolate composition. The enolate formed from 2,2-dimethyl-3-pentanone under kinetically controlled conditions is the Z-isomer.5 When it reacts with benzaldehyde only the syn aldol is formed.4 The product stereochemistry is correctly predicted if the TS has a conformation with the phenyl substituent in an equatorial position. 

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