Carbonyl compounds, condensation reactions aldol dehydration

Condensations are some of the most important enolate reactions of carbonyl compounds. Condensations combine two or more molecules, often with the loss of a small molecule such as water or an alcohol. Under basic conditions, the aldol condensation involves the nucleophilic addition of an enolate ion to another carbonyl group. The product, a /3-hydroxy ketone or aldehyde, is called an aldol because it contains both an aldehyde group and the hydroxy group of an alcoho/. The aldol product may dehydrate to an a,/3-unsaturated carbonyl compound. 

One cannot help but notice that the above reactions lead to related products characterized by the presence of two oxygens in a 1,3-relationship as either a jS-hydroxycarbonyl (if both components are aldehyde or ketones) or a )S-dicarbonyl system (in the case of esters). Both of these functionalities are useful in subsequent conversions and we see that the synthetic utility of the reactions used to prepare these adducts is broadened further. Typical transformations are shown in Scheme 2.26 for the product 70 of an acetone aldol condensation. Oxidation of 70 leads to the formation of the corresponding dicarbonyl compounds 71, while the 1,3-diol 72 is formed as a result of reduction of 70 and the a,j8-unsaturated carbonyl compound 73, formed via dehydration of 70. 

Aldol condensation (Section 24. IB) An aldol reaction in which the initially formed P-hydroxy carbonyl compound loses water by dehydration. 

One of the most ancient C-C bond transformation in organic chemistry is the useful aldol reaction [1, 2], originally reported by Wurtz in 1872 [lb]. Years before this process was described, Kane discovered the related aldol condensation [la]. In this case, a,p-unsaturated carbonyl compound was obtained by dehydration of the former aldol product. In the aldol reaction, a nucleophile, generally an enolizable carbonyl compound, reacts with itself or with another carbonyl compound acting as electrophile to give a P-hydroxy carbonyl compound... 

In acid, a second reaction, the dehydration of the p-hydroxy carbonyl compound to the a,P unsaturated aldehyde or ketone is very common, and it is generally the dehydrated products that are isolated (Fig. 19.69). In the overall reaction, two carbonyl compounds condense to produce a larger carbonyl compound and give off a small molecule— water in this case. Thus, the aldol reaction is often called the aldol condensation. 

Aldol additions and ester condensations have always been and still are the most popular reactions for the formation of carbon-carbon bonds (A.T. Nielsen, 1968). The earbonyl group acts as an a -synthon, the enoi or enolate as a d -synthon. Both reactions will be treated together here, and arguments, which are given for aldol additions, are also valid for ester condensations. Many famous name reactions belong to this category ). The products of aldol additions may be either /J-hydroxy carbonyl compounds or, after dehydration, or, -unsaturated carbonyl compounds. 

The addition of the a-carbon of an enolizable aldehyde or ketone 1 to the carbonyl group of a second aldehyde or ketone 2 is called the aldol reaction It is a versatile method for the formation of carbon-carbon bonds, and is frequently used in organic chemistry. The initial reaction product is a /3-hydroxy aldehyde (aldol) or /3-hydroxy ketone (ketol) 3. A subsequent dehydration step can follow, to yield an o ,/3-unsaturated carbonyl compound 4. In that case the entire process is also called aldol condensation. 

Iminium ions are intermediates in a group of reactions that form ,( -unsaturated compounds having structures corresponding to those formed by mixed aldol addition followed by dehydration. These reactions are catalyzed by amines or buffer systems containing an amine and an acid and are referred to as Knoevenagel condensations,2U The reactive electrophile is probably the protonated form of the imine, since it is a more reactive electrophile than the corresponding carbonyl compound.212... 

Crossed aldol condensations, where both aldehydes (or other suitable carbonyl compounds) have a-H atoms, are not normally of any preparative value as a mixture of four different products can result. Crossed aldol reactions can be of synthetic utility, where one aldehyde has no a-H, however, and can thus act only as a carbanion acceptor. An example is the Claisen-Schmidt condensation of aromatic aldehydes (98) with simple aliphatic aldehydes or (usually methyl) ketones in the presence of 10% aqueous KOH (dehydration always takes place subsequent to the initial carbanion addition under these conditions) ... 

The third hypothesis (C) is that reaction takes place through an aldol condensation between the ethyl acetoacetate and the carbonyl form of the sugar. There is some precedent indicating that it is possible for /3-ketonic esters to undergo aldol condensation. These compounds react mole to mole with the aliphatic aldehydes and afford unsaturated substances, which could be formed via an aldol condensation with subsequent dehydration. 

This aldol condensation is assumed to proceed via nucleophilic addition of a ruthenium enolate intermediate to the corresponding carbonyl compound, followed by protonation of the resultant alkoxide with the G-H acidic starting nitrile, hence regenerating the catalyst and releasing the aldol adduct, which can easily dehydrate to afford the desired a,/3-unsaturated nitriles 157 in almost quantitative yields. Another example of this reaction type was reported by Lin and co-workers,352 whereas an application to solid-phase synthesis with polymer-supported nitriles has been published only recently.353... 

Aldol addition and condensation reactions involving two different carbonyl compounds are called mixed aldol reactions. For these reactions to be useful as a method for synthesis, there must be some basis for controlling which carbonyl component serves as the electrophile and which acts as the enolate precursor. One of the most general mixed aldol condensations involves the use of aromatic aldehydes with alkyl ketones or aldehydes. Aromatic aldehydes are incapable of enolization and cannot function as the nucleophilic component. Furthermore, dehydration is especially favorable because the resulting enone is conjugated with the aromatic ring. 

Mechanistic studies of the Erlenmeyer reaction suggest that the reaction proceeds through initial rapid and reversible formation of the saturated oxazolone followed by an aldol condensation of the latter with the carbonyl compound and subsequent dehydration. ... 

The forward synthetic reaction is a base-catalysed condensation reaction between two carbonyl compounds, the aldol condensation leading to -hydroxy-aldehydes or / -hydroxyketones followed by dehydration. This sequence is one of the most important carbon-carbon bond forming reactions, and aldol-type condensation reactions are considered in a number of other sections of the text, for example, the Doebner reaction (Section 5.18.3, p. 805), the Knoevenagel reaction (Section 5.11.6, p. 681), the Perkin reaction (Section 6.12.3, p. 1036) and the Robinson annelation reaction (Section 7.2). 

The carbon alpha to the carbonyl of aldehydes and ketones can act as a nucleophile in reactions with other electrophilic compounds or intermolecu-larly with itself. The nucleophilic character is imparted via the keto-enol tau-tomerism. A classic example of this reactivity is seen in the aldol condensation (41), as shown in Figure 23. Note that the aldol condensation is potentially reversible (retro-aldol), and compounds containing a carbonyl with a hydroxyl at the (3-position will often undergo the retro-aldol reaction. The aldol condensation reaction is catalyzed by both acids and bases. Aldol products undergo a reversible dehydration reaction (Fig. 23) that is acid or base catalyzed. The dehydration proceeds through an enol intermediate to form the a,(3-unsaturated carbonyl containing compound. 

This is a general reaction exhibited by aldehydes and ketones having labile (usually a) hydrogen atoms. The hydrogen atom of one molecule of the carbonyl compound adds to the carbonyl group of another molecule of the same or different compound to form an aldol (hydroxy aldehyde) or a ketol (hydroxy ketone). The condensation is reversible and is usually promoted by basic catalysts. The products are distilled at temperatures as low as possible to prevent not only the reverse reaction but also the dehydration to olefinic compounds (method 36). 

The aldol condensation involves the reaction of two molecules of an aldehyde or ketone that has alpha hydrogens. Abstraction of an alpha hydrogen by base produces a carbanion which attacks the carbonyl carbon of the other molecule by base-initiated nucleophilic addition an alcohol group is formed. Often the alcohol dehydrates to form the final product, an unsaturated aldehyde or ketone. In a crossed aldol condensation, a carbonyl compound with alpha hydrogens reacts with one without alpha hydrogens. 

The aldol condensation reaction is the acid- or base-catalyzed self-condensation of a ketone or aldehyde.Under certain conditions, the reaction product may undergo further transformations, especially dehydration. The reaction may also occur between two different carbonyl compounds, in which case the term mixed aldol condensation is applied. The mechanistic pattern of the reaction, involving attack by... 

Aldol Reaction (Condensation) [24] Traditionally, it is the acid- or base-catalyzed condensation of one carbonyl compound with the enolate/enol of another, which may or may not be the same, to generate a P-hydroxy carbonyl compound— an aldol. The method is composed of self-condensation, polycondensation, generation of regioisomeric enols/enolates, and dehydration of the aldol followed by Michael addition, q.v. The development of methods for the preparation and use of preformed enolates or enol derivatives that dictate specific caibon-caibon bond formation have revolutionized the coupling of carbonyl compounds (Fig. 6.6) ... 

Formation of (x,/3-Unsaturated Compounds by Dehydration of Aldol Products. As previously stated, the /9-hydroxy carbonyl product of the aldol condensation is thermod5mamically unfavored at high temperatures. Under these conditions, the /9-hydroxy carbonyl is hardly found among the reaction products because it is readily converted to the corresponding o, y0-unsaturated carbonyl compound by dehydration on acid and bases. However, the dehydration step will only take place if the reactant molecule that supplies the carbanion initially contains a second a-hydrogen, in other words, a methylenic group. Thus, in Scheme 1, at least one of substituents R4 and R5 is required to be a hydrogen atom. 

Tables 1 and 2 show some examples of self- or cross-aldol condensation reactions followed by dehydration to obtain a,/3-unsaturated carbonyl compounds. Also in Table 1, a review of methyl isobutyl ketone (a saturated ketone) synthesis in the presence of hydrogen is included (10). In Table 2, some examples of fine chemicals obtained by aldol-type reactions are shown.

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