Enolate Reactions with Carbonyl Groups

The decarboxylation reaction usually proceeds from the dissociated form of a carboxyl group. As a result, the primary reaction intermediate is more or less a carbanion-like species. In one case, the carbanion is stabilized by the adjacent carbonyl group to form an enolate intermediate as seen in the case of decarboxylation of malonic acid and tropic acid derivatives. In the other case, the anion is stabilized by the aid of the thiazolium ring of TPP. This is the case of transketolases. The formation of carbanion equivalents is essentially important in the synthetic chemistry no matter what methods one takes, i.e., enzymatic or ordinary chemical. They undergo C—C bond-forming reactions with carbonyl compounds as well as a number of reactions with electrophiles, such as protonation, Michael-type addition, substitution with pyrophosphate and halides and so on. In this context,... 

It seems unlikely that this reaction could occur in quite the same way as in the laboratoryaldol reaction, because the enolate anion of the donor molecule (dihydroxypropanone) is not expected to be formed in significant amount of the pH of living cell. In fact there is strong evidence that the enzyme behaves as amino (ENH2) compound and reacts with carbonyl group of dihydroxy propanone to form an imine. This implies that the imine form of dihydroxy propanone is a key intermediate in the overall aldol-type addition. 

Careful investigation of the bromination reaction of 3 keto steroids, which leads ultimately to 2,4-dibromo derivatives (see, for example, S-2-5-3), revealed that the sequence starts with the formation of a 2a bromo derivative, a futher demonstration of the preferred enolization of the carbonyl group toward the 2 position. 

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. 

With an acceptor-substituted alkene moiety tethered to the molecule, the intermediate silyl enol ether may undergo an intramolecular [2-I-2] cycloaddition.The silyl-assisted addition of hydrogen halides to cyclopropanes is not restricted to ketones with carbonyl groups as activating function or iodide as nucleophile. Esters and other acid derivatives underwent similar reactions when treated with iodotrimethylsilane alone or in the presence of an additional catalyst such as mercury(II) or zinc(II) chloride.Subsequent treatment of the y-iodo ester with potassium carbonate in tetrahydrofuran gave the respective y-butyrolactones in good yield. 

Sn -mediated reactions. Apparently, Li, Zn and Sn overcome thermodynamic dipolar forces which favor the ( ,Z)-orientation through chelation involving the enolate and both carbonyl groups. Without loss of ligand (L), boron or Sn" cannot bind simultaneously the three oxygen atoms from the enolate and the two carbonyls in these cases, the reaction proceeds primarily through a template similar to T with the ( ,Z)-orientation to provide predominantly (131). 

The carbonyl group is one of the most prevalent of the functional groups and is involved in many synthetically important reactions. Reactions involving carbonyl groups are also particularly important in biological processes. Most of the reactions of aldehydes, ketones, esters, carboxamides, and the other carboxylic acid derivatives directly involve the carbonyl group. We discussed properties of enols and enolates derived from carbonyl compounds in Chapter 6. In the present chapter, the primary topic is the mechanisms of addition, condensation and substitution reactions at carbonyl centers. We deal with the use of carbonyl compounds to form carbon-carbon bonds in synthesis in Chapters 1 and 2 of Part B. 

Compounds ofher fhan phenols are also capable of giving color reactions with iron(III). Of special inferesf are fhe ones forming red or violet complexes formate and acetate, benzoate, acetylacetone, and antipyrine. Even some steroids can give red complexes with iron(lll) through enolization of a carbonyl group.Selectivity in the test method is given by the color of fhe complex and its stability even after adding acetic acid. 

With unsymmetrical ketones, a mixture of regioisomeric enolates may be formed, resulting in a mixture of Michael adducts. Deprotonation in a protic solvent is reversible and leads predominantly to the thermodynamically favoured, more-substituted enolate. Reaction with a Michael acceptor then gives the product from reaction at the more-substituted side of the ketone carbonyl group. The 1,5-dicarbonyl compound 24 is the major product from conjugate addition of 2-methylcyclohexanone to methyl acrylate using potassium tert-butoxide in the protic solvent tert-butanol (1.39). In contrast, the major product from Michael addition... 

The situation becomes a little more complex if the aldehyde contains a chiral centre, as in 2-phenylpropanal. In such cases, the aldol product formed contains three chiral centres and there are four possible diastereoisomers - two 2,3-syn and two 2,3-anti isomers (and their enantiomeric pairs, thereby totalling eight stereoisomers) (1.69). The relative stereochemistry of the substituents at C-2 and C-3 is controlled by the geometry of the enolate. The C-3,C-4 stereochemistry, on the other hand, depends on the direction of approach of the enolate and the carbonyl group to each other. This is illustrated in Scheme 1.70, for the reaction of 2-phenylpropanal with the trans-enolate of 2,6-dimethylphenyl propionate. 

The first stage in fatty acid biosynthesis is a condensation between acetyl CoA (the starter unit) and malonyl CoA with the loss of CO2. This reaction could be drawn like this, with CO2 being lost as the new C—C bond is formed. When chemists use malonates, we like to make the stable enol using both carbonyl groups, condense, and only afterwards release CO2 (Chapter 25). As you saw on p. 1158, nature does this in making acetoacetyl CoA during alkaloid biosynthesis, but here things work differently. 

The chemistry of carbohydrates has sometimes been referred to as a marriage between the chemistry of alcohols and that of aldehydes and ketones. In the preceding sections, we examined oxidations and reductions of carbohydrates, cyanohydrin formation, Fischer glycosidation, and processes that involve enolization. All of these reactions involve carbonyl groups in carbohydrates. In this section, we will consider the reactions of the hydroxyl groups of carbohydrates, starting with their conversion to esters. 

An aldol reaction begins with addition of an enolate or enol to the carbonyl group of an aldehyde or ketone, leading to a j8-hydroxy aldehyde or ketone as the initial product. A simple example is shown below, whereby two molecules of acetaldehyde (ethanal) react to form 3-hydroxybutanal. 3 Hydroxybutanal is an aldol because it contains both an aldehyde and an alcohol functional group. Reactions of this general type are known as aldol additions. 

There is also an acid-catalyzed version of the Michael reaction. In this reaction the carbonyl group is initially protonated, and the carbon-carbon double bond is then attacked by a nucleophile to give the enol (Fig. 19.83). The enol equilibrates with the more stable carbonyl compound to produce the final product of addition. 

However, a little thought about the mechanism reveals potential problems. Two enolates can be formed and each enolate has two carbonyl groups to attack (Fig. 19.90). Thus, four products. A, B, C, and D, are possible (more if any of the (3-hydroxy ketones are dehydrated to a,(3-unsaturated ketones), and all are likely to be formed in comparable yield. The enolate of diethyl ketone can add to the carbonyl of acetone or diethyl ketone to give A and B. Similarly, the enolate of acetone gives C and D by reaction with the two carbonyl compounds. 

Treatment of methoxymethyltrimethylsilane with BuTi in THF gives methoxy-(trimethylsilyl)methyllithium, and its subsequent reactions with carbonyl compounds have been reported to afford the adducts, a-methoxy-j8-hydroxyalkylsilanes 58 (Scheme 2.38). Although the initial adducts do not undergo elimination of a silyl group in situ, the corresponding enol ethers 59 are formed upon treating... 

Silyl(methoxy)benzotriazol-l-ylmethane 62 is lithiated with BuLi to give the corresponding anion, which undergoes Peterson reactions with carbonyl compounds (Scheme 2.40) [100, 101]. The products, l-(l-methoxy-l-alkenyl)benzotriazoles 63, are synthetically equivalent to an acylbenzotriazole synthon in which the carbonyl group is masked as an enol ether [102, 103]. Transformation of the alkenyl ethers into carboxyhc acids is readily achieved by treatment with zinc bromide and hydrochloric add in refluxing 1,4-dioxane [104]. 

Next, let s consider a problem similar to we encountered for mixed aldol condensations. Which a-catbon atom will react with which carbonyl carbon atom if rings of similar size could result Under the reaction conditions, all possible enolates can form in low concentration. Thus, we can consider the various carbonyl groups and determine which is more likely to react with the nucleophilic carbon atom of an enolate. If one carbonyl group is an aldehyde and the other a ketone, the answer to the question is easy because the aldehyde carbonyl group is more susceptible to attack by a nucleophile. 

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