Enolate reactions, carbonyl groups

This complex transform can be envisaged by assuming that one equivalent of 3-8 attacks the enol lactone carbonyl group to afford the hydroxylactone 4-2 (Scheme 4.4). This unstable intermediate actually comprises a hemiacetal of an enol lactone. The reaction medium is sufficiently basic to cause the underlying diketone (4-3) to undergo aldol cyclization to form cyclohexenone 4-4. 

This chapter is about deliberately getting nucleophilic attack by enols and enolates on carbonyl groups of aldehydes or ketones (the aldol reaction in the first half of the chapter) or on acylating agents (the second half of the chapter). 

The aldol addition of butanal is shown in Mechanism 20.1. The enolate is formed in the first step by deprotonation of the a carbon. At this point, the reaction mixture contains both the aldehyde and its enolate. The carbonyl group of the aldehyde is electrophilic the enolate is nucleophilic. This complementary reactivity leads to nucleophilic addition of the enolate to the carbonyl group (step 2). This is the step in which the new carbon-carbon bond forms to give the alkoxide ion corresponding to the aldol. Proton transfer from the solvent (water) completes the process (step 3). The product of the aldol addition of butanal contains two chirality centers however, it is racemic because the reactants are achiral. 

The Mannich reaction apparently proceeds through a variety of mechanisms depending on the reactants and the conditions that are employed. The mechanism below appears to operate in neutral or acidic media. Note the aspects in common with imine formation and with reactions of enols and carbonyl groups. 

The addition of carbon nucleophiles, including organometallic compounds, enolates, and enols, to carbonyl groups is one of the main methods of formation of carbon-carbon bonds. Such reactions are extremely important in synthesis and will be discussed extensively in Part B. Here, we will examine some of the fundamental mechanistic aspects of addition of carbon nucleophiles to carbonyl groups. 

Enolates are powerful carbon nucleophiles and addition of enolates to carbonyl groups (aldol reactions) serve as a useful method for C-C bond formation. The Mukaiyama aldol reactions involving fluoride ion-promoted addition of silyl enolates to aldehydes are very popular and are frequently employed in the construction of carbon skeletons in organic synthesis [ 1 ]. The Mukaiyama aldol reaction with the silyl enol ether of cyclohexanone and 4-bromobenzaldehyde can be performed based on the electroosmotic flow (EOF) technique with a four-chaimel microstructured flow reactor (charmel dimensions 100 x 50pm). The reactor was prepared using a standard fabrication procedure developed at the University of Hull [2, 3]. Based on GC-MS analysis, quantitative conversion of the starting material was achieved in 20 min, whereas in the case with a traditional batch system a quantitative yield was obtained only when an extended reaction time of 24 h was employed (Figure 5.1). 

A completely different rationale for the stereochemical outcome of aldol additions relies on open-transition-state models. These involve anti-periplanar orientation of enolate and carbonyl group, in contrast with their syn-clinal conformation assumed in the six-membered cyclic transition states. Open-transition-state structures have been proposed to offer a rationale for those aldol additions that give predominantly syn products, irrespective of enolate geometry [90]. This outcome has been observed in aldol reactions of tin and zirconium enoiates and of naked enoiates generated from enolsilanes by treatment with tris(diethylamino)sulfonium difluoro-methylsiliconate [70]. As shown in Scheme 1.12, the driving force for the... 

So far in this section we have combined enolate anions with other carbonyl compounds by direct attack at the carbonyl group. We can expand the scope of this reaction by using a,p-unsaturated carbonyl compounds as the electrophiles. This is the Michael reaction. Remind yourself of tliis by writing out the mechanism of a Michael reaction such as ... 

In the preceding chapter you learned that nucleophilic addition to the carbonyl group IS one of the fundamental reaction types of organic chemistry In addition to its own reactivity a carbonyl group can affect the chemical properties of aldehydes and ketones m other ways Aldehydes and ketones having at least one hydrogen on a carbon next to the carbonyl are m equilibrium with their enol isomers... 

With certain other nucleophiles addition takes place at the carbon-carbon double bond rather than at the carbonyl group Such reactions proceed via enol intermediates and are described as conjugate addition ox 1 4 addition reactions... 

A reaction of great synthetic val ue for carbon-carbon bond for mation Nucleophilic addition of an enolate ion to a carbonyl group followed by dehydration of the 3 hydroxy aldehyde yields an a p unsaturated aldehyde... 

As we saw m Chapter 20 thioesters are more reactive than ordinary esters toward nucleophilic acyl substitution They also contain a greater proportion of enol at equilib rmm Both properties are apparent m the properties of acetyl coenzyme A In some reactions it is the carbonyl group of acetyl coenzyme A that reacts m others it is the a carbon atom... 

Aldol Addition and Related Reactions. Procedures that involve the formation and subsequent reaction of anions derived from active methylene compounds constitute a very important and synthetically useful class of organic reactions. Perhaps the most common are those reactions in which the anion, usually called an enolate, is formed by removal of a proton from the carbon atom alpha to the carbonyl group. Addition of this enolate to another carbonyl of an aldehyde or ketone, followed by protonation, constitutes aldol addition, for example... 

Study of the mechanism of this complex reduction-Hquefaction suggests that part of the mechanism involves formate production from carbonate, dehydration of the vicinal hydroxyl groups in the ceUulosic feed to carbonyl compounds via enols, reduction of the carbonyl group to an alcohol by formate and water, and regeneration of formate (46). In view of the complex nature of the reactants and products, it is likely that a complete understanding of all of the chemical reactions that occur will not be developed. However, the Hquefaction mechanism probably involves catalytic hydrogenation because carbon monoxide would be expected to form at least some hydrogen by the water-gas shift reaction. 

Substitution reactions by the ionization mechanism proceed very slowly on a-halo derivatives of ketones, aldehydes, acids, esters, nitriles, and related compounds. As discussed on p. 284, such substituents destabilize a carbocation intermediate. Substitution by the direct displacement mechanism, however, proceed especially readily in these systems. Table S.IS indicates some representative relative rate accelerations. Steric effects be responsible for part of the observed acceleration, since an sfp- caibon, such as in a carbonyl group, will provide less steric resistance to tiie incoming nucleophile than an alkyl group. The major effect is believed to be electronic. The adjacent n-LUMO of the carbonyl group can interact with the electnai density that is built up at the pentacoordinate carbon. This can be described in resonance terminology as a contribution flom an enolate-like stmeture to tiie transition state. In MO terminology,.the low-lying LUMO has a... 

Enolates can also serve as carbon nucleophiles in carbonyl addition reactions. The addition reaction of enolates with carbonyl compounds is of very broad scope and is of great synthetic importance. Essentially all of the enolates considered in Chapter 7 are capable of adding to carbonyl groups. The reaction is known as the generalized aldol addition. 

Because the pK s of the aldehyde and water are similar, the solution contains significant quantities of both the aldehyde and its enolate. Moreover, their reactivities are complementary. The aldehyde is capable of undergoing nucleophilic addition to its carbonyl group, and the enolate is a nucleophile capable of adding to a carbonyl group. And as shown in Figure 18.4, this is exactly what happens. The product of this step is an alkoxide, which abstracts a proton from the solvent (usually water or ethanol) to yield a (3-hydroxy aldehyde. A compound of this type is known as an aldol because it contains both an aldehyde function and a hydroxyl group (aid + ol = aldol). The reaction is called aldol addition. 

FIGURE 19.13 (a) A mechanism for the fructose-l,6-bisphosphate aldolase reaction. The Schlff base formed between the substrate carbonyl and an active-site lysine acts as an electron sink, Increasing the acidity of the /3-hydroxyl group and facilitating cleavage as shown. (B) In class II aldolases, an active-site Zn stabilizes the enolate Intermediate, leading to polarization of the substrate carbonyl group. 

A recent paper by Singh et al. summarized the mechanism of the pyrazole formation via the Knorr reaction between diketones and monosubstituted hydrazines. The diketone is in equilibrium with its enolate forms 28a and 28b and NMR studies have shown the carbonyl group to react faster than its enolate forms.Computational studies were done to show that the product distribution ratio depended on the rates of dehydration of the 3,5-dihydroxy pyrazolidine intermediates of the two isomeric pathways for an unsymmetrical diketone 28. The affect of the hydrazine substituent R on the dehydration of the dihydroxy intermediates 19 and 22 was studied using semi-empirical calculations. ... 

In general the reaction of an aldehyde with a ketone is synthetically useful. Even if both reactants can form an enol, the a-carbon of the ketone usually adds to the carbonyl group of the aldehyde. The opposite case—the addition of the a-carbon of an aldehyde to the carbonyl group of a ketone—can be achieved by the directed aldol reaction The general procedure is to convert one reactant into a preformed enol derivative or a related species, prior to the intended aldol reaction. For instance, an aldehyde may be converted into an aldimine 7, which can be deprotonated by lithium diisopropylamide (EDA) and then add to the carbonyl group of a ketone ... 

The third major reaction of carbonyl compounds, alpha substitution, occurs at the position next to the carbonyl group—the alpha (a) position. This reaction, which takes place with all carbonyl compounds regardless of structure, results in the substitution of an a hydrogen by an electrophile through the formation of an intermediate enol or enolcite ion ... 

Although the carbonyl condensation reaction appears different from the three processes already discussed, it s actually quite similar. A carbonyl condensation reaction is simply a combination of a nucleophilic addition step and an -substitution step. The initially formed enolate ion of one acetaldehyde molecule acts as a nucleophile and adds to the carbonyl group of another acetaldehyde molecule, as shown in Figure 5. 

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