Dehydration of an Aldol Product

Dehydration of an aldol product is no more than a functional group interconversion, so the retrosynthesis of a a,P-unsaturated ketone or aldehyde involves making the same disconnection as used for a P-hydroxy ketone or aldehyde between the alpha and beta carbons. It may help to start the retrosynthesis by adding water back in (undoing the dehydration step) to give the more recognizable P-hydroxy carbonyl compound before making the disconnection. 

The Mixed Aldol Reaction and Regiocontrol Involving Enolates 

The aldol examples shown above are described as self -condensations because they involve the reaction of a single carbonyl compound acting as both the nucleophile and the electrophile. The reaction of two different carbonyls presents a problem of c/icmose/ecftVify Which carbonyl will act as the nucleophile, and which will act as the electrophile Mixing two ketones in the presence of a mild base, for example, could give a mixture of four aldol products two cross-condensations and two self-condensations. Since acetone and 3-pentanone have similar reactivities, we would expect all possible combinations to occur. 

To exert control over a mixed aldol, a stepwise approach is required. A strong base, such as LDA (-TS C), can be used to irreversibly form an enolate (Nu ), to which an electrophile can be added. Since a single nucleophile is reacting with a single electrophile, a single aldol product can be expected. 

Complimentary methods are available if the thermodynamic enolate (the more stable enolate) is required, such as forming the silyl enol ether. The silyl enol ether is an enol/enolate equivalent that will react with carbonyl electrophiles in the presence of a Lewis acid catalyst, such as TiCL- 

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The correct mechanism for the base-catalyzed dehydration of an aldol product requires two steps ... 

Do not draw a concerted E2 reaction for the dehydration of an aldol product. 

A common method for forming alkenes by -elimination involves the dehydration of an aldol product (see Section 1.1.3). Under appropriate conditions or with suitable substituents, both the aldol reaction and the dehydration steps can be carried out in the same pot. For example, elimination occurs in situ to give the conjugated alkene chalcone, on aldol condensation between acetophenone and benzaldehyde (2.11). This reaction works well, as only one component (acetophenone) is enoUz-able and as benzaldehyde is more electrophilic. Mixtures of products result from... 

Hydroxyaldehydes and /3-hydroxyketones are very easily dehydrated, and often the conditions necessary to bring about an aldol reaction are sufficient to cause dehydration (Section 8.2E). Dehydration can also be brought about by warming the aldol product in dilute acid. The major product from the dehydration of an aldol product is one in which the carbon—carbon double bond is conjugated with the carbonyl group that is, the product... 

The product of dehydration of an aldol product is always an a, 3-unsaturated carbonyl compound. The C—C double bond always forms between the a-carbon and the carbon that was once bonded to the —OH group. 

The location of the OH leaving group in a position that is beta to a carbonyl, along with the formation of a stable, conjugated pi bond, makes this reaction much easier than a dehydration of an ordinary alcohol. The dehydration of an aldol product requires much milder reaction conditions than a typical alcohol, and can even occur spontaneously at room temperature. For example, in the reaction of benzaldehyde with acetone, the double aldol product shown is the only one isolated the presence of the two benzene rings makes the newly formed pi bonds highly conjugated and very stable. 

Acid-Catalyzed Dehydration of an Aldol Product (Section 19.2A)... 

Heating a basic or acidic mixture of an aldol product leads to dehydration of the alcohol... 

Heating a basic or acidic mixture of an aldol product leads to dehydration of the alcohol functional group. The product is a conjugated a,/3-unsaturated aldehyde or ketone. Thus, an aldol condensation, followed by dehydration, forms a new carbon-carbon double bond. Before the Wittig reaction was discovered (Section 18-13), the aldol with dehydration was probably the best method for joining two molecules with a double bond. It is still often the cheapest and easiest method. 

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). 

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 (alk e < /dehyde) or enone (alk e kem ), 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. 

Identify all the alpha hydrogens in the molecule, and for each one, form an enolate anion. Then decide which enolate anion would form the more stable ring upon reaction with the other carbonyl in the molecule. It often helps to number the atoms in the ketone or aldehyde.The product of dehydration of any aldol product is always an a,j3-unsaturated carbonyl compound. The C — C double bond always forms between the a-carbon and the carbon that was once bonded to the —OH group. 

Show how to prepare each a,/3-unsaturated ketone by an aldol reaction followed by dehydration of the aldol product (See Examples 15.2,15.3)... 

If the aldol reaction mixture is heated under basic conditions, the dehydrated product forms. The dehydration of the aldol under basic reaction conditions drives reaction to completion. The aldol may also be isolated and dehydrated hke any other alcohol by using a strong acid. The mechanism of acid-catalyzed dehydration of an aldol is exacdy hke that of alcohols. However, the base-catalyzed dehydration that occurs in the aldol reaction is an E2 process that does not occur for simple alcohols. The base-catalyzed dehydration reaction occurs in two steps. 

The spiroindolinobenzopyran 2 is a classical example of spiropyran and is easily prepared by the condensation of l,3,3-trimethyl-2-methyleneindo-line (Fischer s base) and salicylaldehyde in anhydrous ethanol or benzene (Scheme 2).ia The nucleophilic attack of Fischer s base on the carbonyl group (like an enamine) gives an aldol product, which undergoes ring closure followed by dehydration. This condensation is reversible therefore, an exchange of the salicylaldehyde component of spiropyran with a different salicylaldehyde is possible. For example, when a solution of spiropyran 2 (Scheme 2) was refluxed with 3,5-dinitro-substituted salicylaldehyde, the open form of 6,8-dinitro-BIPS was obtained.2... 

The aldol formed by the aldol reaction, especially if heated, can react further. The heating causes dehydration (loss of H2O), and the overall reaction involving an aldol reaction followed by dehydration is the aldol condensation. The product of an aldol condensation, favored by the presence of extended conjugation, is an a,(3-unsaturated aldehyde (an enal) or ketone. The mechanism for dehydration (Figure 11-13) begins where the mechanism of the aldol reaction (Figure 11-12) ends. This process works better if extended conjugation results. The aldol reaction and condensation are reversible. 

Formylfuran behaves in a very similar manner to benzaldehyde and undergoes the usual reactions of an aromatic aldehyde, e.g. (i) the Cannizzaro reaction with cone, sodium hydroxide to give furan-2-ylmethanol and the sodium salt of furoic acid, (ii) the Perkin reaction with acetic anhydride and sodium acetate to yield an aldol product that dehydrates to 3-(furan-2-yl)propenoic acid, and (iii) a condensation with potassium cyanide in alcoholic solution to form furoin (under these conditions, benzaldehyde undergoes the benzoin condensation) (Scheme 6.32). 

As long as we remember their limitations, aldol condensations can serve as useful synthetic reactions for making a variety of organic compounds. In particular, aldol condensations (with dehydration) form new carbon-carbon double bonds. We can use some general principles to decide whether a compound might be an aldol product and which reagents to use as starting materials. 

Aldol condensations produce /3-hydroxy aldehydes and ketones (aldols) and a,/3-unsaturated aldehydes and ketones. If a target molecule has one of these functionalities, an aldol should be considered. To determine the starting materials, divide the structure at the a, (3 bond. In the case of the dehydrated product, the a,(3 bond is the double bond. The following analyses show the division of some aldol products into their starting materials. 

This NADPH reaction is typically stereo- and chemoselective, though the stereochemistry is rather wasted here as tile next step is a dehydration, typical of what is now an aldol product, and occurring by an enzyme-catalysed ElcB mechanism. 

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. 

Dehydration of the initial P-hydroxy carbonyl compound drives the equilibrium of an aldol reaction to the right, thus favoring product formation. Once the conjugated a,p-unsaturated carbonyl compound forms, it is not re-converted to the P-hydroxy carbonyl compound. 

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