Condensation reactions, carbonyl compounds enolization

Alpha substitutions and condensations of carbonyl compounds are some of the most common methods for forming carbon-carbon bonds. These types of reactions are common in biochemical pathways, particularly in the biosynthesis and metabolism of carbohydrates and fats. A wide variety of compounds can participate as nucleophiles or electrophiles (or both) in these reactions, and many useful products can be made. We begin our study of these reactions by considering the structure and formation of enols and enolate ions. 

Addition of carbon nucleophiles to the C=C bond of a compound la,b includes reactions of enolizable carbonyl compounds, enol ethers, and ena-mines, as well as lithium alkyls and zinc alkyls. Condensation of the enolizable ketone 68 with la,b (M = Cr, W)26 is induced, for example, by catalytic amounts of triethylamine in pentane and under these conditions affords a 90% yield of crystalline pyranylidene complex 57 directly from the reaction mixture.102 This reaction proceeds via the 2-ethoxy-l-metallatriene L, which, because of the presence of triethylamine, rapidly undergoes ring closure to the pyranylidene (pyrylium ylide) complex 69 by 1,6-elimination of ethanol (Scheme 22). Chromanylidene complexes 71 are obtained from condensation of a /3-tetraIone 70 (R = H, OMe) with compound 1a,b. 

Allylation andaldol reaction. Diallylstannane and silyl enol ethers condense with carbonyl compounds to furnish homoallylic alcohols and p-hydroxy ketones, respectively. A mixture of HjO, EtOH, and toluene is a suitable reaction medium as CufOTflj is stable in water. 

Hydroxy aldehydes. On treatment with MeLi and then (BuO)4Ti, silyl enol ethers of aldehydes form enoxytitanates that condense with carbonyl compounds. It should be emphasized that in conventional aldol reactions aldehydes behave as acceptors. In this method, the donor role is established. 

Mixed condensations in which the nucleophilic enolate is derived from an ester have also been developed. Very strong bases have usually been used for enolate formation. For example, the lithium enolate of ethyl acetate is generated using lithium bis(trimethylsilyl)amide as the base. Condensation with carbonyl compounds proceeds readily (entry 13, Scheme 2.1) without apparent complications from proton-transfer reactions between the ester enolate and carbonyl compound. The dilithium salts of carboxylic acids can also add to carbonyl compounds (entry 14, Scheme 2.1). 

Many important organic reactions involve nucleophilic carbon species (car-banions). The properties of carbanions will be discussed in detail in Chapter 7 and in Part B, Chapters 1 and 2. Most C-H bonds are very weakly acidic and have no tendency to form carbanions spontaneously. Reactions that involve carbanion species are therefore often carried out by reaction of a neutral organic molecule with an electrophile in the presence of a base. Under these conditions, a nucleophilic carbon species is formed when the base abstracts a proton from the neutral organic molecule. Base-catalyzed condensation of carbonyl compounds is an example. The reaction of acetophenone and benzaldehyde which was considered in Section 4.2, for example, requires base catalysis to proceed and the kinetics show that the rate is proportional to the catalyst concentration. This is because the neutral acetophenone molecule is not nucleophilic and does not react with benzaldehyde. The enolate formed by deprotonation is much more nucleophilic and the reaction proceeds through this intermediate. 

The aldol condensation and related reactions are among the most important, and ubiquitous, construction reactions in organic synthesis. In these condensations, the carbonyl compound acts as both nucleophile and electrophile—the enol or enolate is the nucleophile, and the keto form is the electrophile. The reaction works with enolizable aldehydes (Figure 17.24) or ketones (Figure 17.25) and may be catalyzed by either acid or base. Almost all of the steps we write are equilibria—how can we persuade the reaction to go to completion In the base-catalyzed reaction, a catalyst such as barium hydroxide is placed inside a Soxhlet thimble, as in Figure 17.26. The reaction mixture is heated so that the acetone refluxes, but the product does not. Thus only the SM, and not the product, comes into contact with the catalyst, ensuring that the reverse reaction does not occur. Note that in the acid-catalyzed processes, it is common for the product to be dehydrated under the reaction conditions—this usually pulls the equilibrium over to the product. The mechanism of the elimination reaction may be El or E2 depending on the... 

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 usual base or acid catalyzed aldol addition or ester condensation reactions can only be applied as a useful synthetic reaction, if both carbonyl components are identical. Otherwise complicated mixtures of products are formed. If two different aldehydes or esters are to be combined, it is essential that one of the components is transformed quantitatively into an enol whereas the other component remains as a carbonyl compound in the reaction mixture. 

Fluoroalkyl ketones may be used as the electrophilic partners in condensation reactions with other carbonyl compounds The highly electrophilic hexafluo-roacetone has been used in selective hexafluoroisopropyhdenation reactions with enol silyl ethers and dienolsilyl ethers [f] (equation 1)... 

We ve now studied three of the four general kinds of carbonyl-group reactions and have seen two general kinds of behavior. In nucleophilic addition and nucleophilic acyl substitution reactions, a carbonyl compound behaves as an electrophile. In -substitution reactions, however, a carbonyl compound behaves as a nucleophile when it is converted into its enol or enolate ion. In the carbonyl condensation reaction that we ll study in this chapter, the carbonyl compound behaves both as an electrophile and as a nucleophile. 

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. 

There is no simple answer to this question, but the exact experimental conditions usually have much to do with the result. Alpha-substitution reactions require a full equivalent of strong base and are normally carried out so that the carbonyl compound is rapidly and completely converted into its enolate ion at a low temperature. An electrophile is then added rapidly to ensure that the reactive enolate ion is quenched quickly. In a ketone alkylation reaction, for instance, we might use 1 equivalent of lithium diisopropylamide (LDA) in lelrahydrofuran solution at -78 °C. Rapid and complete generation of the ketone enolate ion would occur, and no unreacled ketone would be left so that no condensation reaction could take place. We would then immediately add an alkyl halide to complete the alkylation reaction. 

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. 

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... 

T. Akiyama, J. Takaya, H. Kagoshima, One-Pot Mannich-Type Reaction in Water HBF4 Catalyzed Condensation of Aldehydes, Amines, and Silyl Enolates for the Synthesis of (5-Amino Carbonyl Compounds Synlett. 1999,1426-1428. 

Conjugate reduction.1 This stable copper(I) hydride cluster can effect conjugate hydride addition to a,p-unsaturated carbonyl compounds, with apparent utilization of all six hydride equivalents per cluster. No 1,2-reduction of carbonyl groups or reduction of isolated double bonds is observed. Undesirable side reactions such as aldol condensation can be suppressed by addition of water. Reactions in the presence of chlorotrimethylsilane result in silyl enol ethers. The reduction is stereoselective, resulting in hydride delivery to the less-hindered face of the substrate. 

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. 

Aldol Reaction The formation of an aldol (P-hydroxy carbonyl compound) through the catalyzed condensation of an enol/enolate with a carbonyl compound. 

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. 

The enolates of other carbonyl compounds can be used in mixed aldol condensations. Extensive use has been made of the enolates of esters, thioesters, amides, nitriles, and nitroalkanes. Scheme 2.4 gives a selection of such reactions. 

N-Metalated azomethine ylides generated from a-(alkylideneamino) esters can exist as tautomeric forms of the chelated ester enolate (Scheme 11.8). On the basis of the reliable stereochemical and regiochemical selectivities described below, it is clear that the N-metalated tautomeric contributor of these azomethine ylides is important. Simple extension of the above irreversible lithiation method to a-(alkylideneamino) esters is not very effective, and cycloadditions of the resulting lithiated ylides to a,(3-unsaturated carbonyl compounds are not always clean reactions. When the a-(alkylideneamino) esters bear a less bulky methyl ester moiety, or when a,(3-unsaturated carbonyl compounds are sterically less hindered, these species suffer from nucleophihc attack by the organometalhcs, or the metalated cycloadducts undergo further condensation reactions (81-85). 

Mukiayama aldol reactions between silyl enol ethers and various carbonyl containing compounds is yet another reaction whose stereochemical outcome can be influenced by the presence of bis(oxazoline)-metal complexes. Evans has carried out a great deal of the work in this area. In 1996, Evans and coworkers reported the copper(II)- and zinc(II)-py-box (la-c) catalyzed aldol condensation between benzyloxyacetaldehyde 146 and the trimethylsilyl enol ether [(l-ferf-butylthio)vinyl]oxy trimethylsilane I47. b82,85 Complete conversion to aldol adduct 148 was achieved with enantiomeric excesses up to 96% [using copper(II) triflate]. The use of zinc as the coordination metal led to consistently lower selectivities and longer reaction times, as shown in Table 9.25 (Eig. 9.46). 

In the majority of dehydration reactions, heterocyclic compounds are formed, rather than carbocyclic compounds. Many possibilities for formation of carbocyclic compounds exist, but these are important only if (a) the heterocyclic or acyclic tautomers cannot undergo further elimination reactions, or (b) the conditions of reaction greatly favor the formation of an acyclic tautomer capable of affording only the carbocyclic compound. Both five- and six-membered carbocyclic compounds have been isolated, with reductic acid being the compound most frequently reported. Ring closure occurs by an inter-molecular, aldol reaction that involves the carbonyl group and an enolic structure. Many examples of these aldol reactions that lead to formation of carbocyclic rings have been studied.47 As both elimination and addition of a proton are involved, the reaction occurs in both acidic and basic solutions. As examples of the facility of this reaction, pyruvic acid condenses spontaneously to a dibasic acid at room temperature in dilute solution, and such 8-diketones as 29 readily cyclize to form cyclohexenones, presumably by way of 30, either in acid or base. 

In aldol condensation, the enolate anion of one carbonyl compound reacts as a nucleophile, and attacks the electrophilic carbonyl group of another one to form a larger molecule. Thus, the aldol condensation is a nucleophilic addition reaction. 

When two molecules of ester undergo a condensation reaction, the reaction is called a Claisen condensation. Claisen condensation, like the aldol condensation, requires a strong base. However, aqueous NaOH cannot be used in Claisen condensation, because the ester can be hydrolysed by aqueous base. Therefore, most commonly used bases are nonaqueous bases, e.g. sodium ethoxide (NaOEt) in EtOH and sodium methoxide (NaOMe) in MeOH. The product of a Claisen condensation is a P-ketoester. As in the aldol condensation, one molecule of carbonyl compound is converted to an enolate anion when an a-proton is removed by a strong base, e.g. NaOEt. 

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