Reactions at the a Carbon of Carbonyl Compounds Enols and Enolates

CHAPTER 18 REACTIONS AT THE a CARBON OF CARBONYL COMPOUNDS Enols and Enolates... 

Carbonyl compounds such as acetone 10 exist predominantly in the keto form 10 but are in equilibrium with the enol form 11. We shall be more interested in the formation of the enolate anion 13 with base 12 and its reactions at the a-carbon with carbon electrophiles. 

The a-alkylation of carbonyl compounds by their conversion into nucleophilic enoiates or enolate equivalents and subsequent reaction with electrophilic alkylating agents provides one of the main avenues for regio- and stereo-selective formation of carbon-carbon a-bonds. " Classical approaches to a-alkylation typically involve the deprotonation of compounds containing doubly activated methylene or methine groups and having p/iTa values of 13 or below by sodium or potassium alkoxides in protic solvents. Since these conditions lead to monoenolates derived from deprotonation only at the a-site of the substrate, the question of the regioselectivity of C-alkylation does not arise (however, there is competition between C- and 0-alkylation in certain cases). In more recent years, dienolates of p-dicarbonyl compounds have been utilized in -alkylations with excellent success. 

The carbocation that is formed upon protonation of a carbonyl compound can lose H+ from the a-carbon to give an enol. Enols are good nucleophiles. Thus, under acidic conditions, carbonyl compounds are electrophilic at the carbonyl C and nucleophilic at the a-carbon and on oxygen, just like they are under basic conditions. Resonance-stabilized carbonyl compounds such as amides and esters are much less prone to enolize under acidic conditions than less stable carbonyl compounds such as ketones, aldehydes, and acyl chlorides in fact, esters and amides rarely undergo reactions at the a-carbon under acidic conditions. 

Ketones can be oxidatively carbonylated at the a-carbon via enol intermediates using PdCl2 as the catalyst and Q1CI2 as oxidant [122], The initially formed carbonylation products correspond to a-chlorination and a-alkoxycarbonylation. Under the reaction conditions, these compounds undergo further transformations involving C - C cleavage eventually leading to a mixture of esters and an alkyl chloride or (in the case of cyclic ketones) to a diester and a chloroester (Schemes 20-21). 

The point was made earlier (Section 5.9) that alcohols require acid catalysis in order to undergo dehydration to alkenes. Thus, it may seem strange that aldol addition products can be dehydrated in base. This is another example of the way in which the enhanced acidity of protons at the a-carbon atom affects the reactions of carbonyl compounds. Elimination may take place in a concerted E2 fashion or it may be stepwise and proceed through an enolate ion. 

The first step of the Stobbe condensation is the deprotonation of the succinate at the a-carbon to afford an ester enolate that in situ undergoes an aldol reaction with the carbonyl compound to form a 3-alkoxy ester intermediate. The following intramolecular acyl substitution gives rise to a y-lactone intermediate which undergoes ring-opening and concomittant double bond formation upon deprotonation by the alkoxide ion. Under certain conditions the lactone intermediate can be isolated. 

Some carbonyl-based compounds (imines, carboxylic acids) are better electrophiles under acidic conditions than they are under basic conditions. Reactions using these compounds as electrophiles are usually executed under acidic conditions. On the other hand, enolates are always better nucleophiles than enols when carbonyl compounds are required to react with electrophiles that are not particularly reactive, such as esters or alkyl bromides, basic conditions are usually used. Carbonyl compounds that are particularly low in energy (esters, amides) have such a small proportion of enol at equilibrium that they cannot act as nucleophiles at the a-carbon under acidic conditions. Nevertheless, no matter whether acidic or basic conditions are used, carbonyl compounds are always nucleophilic at the a-carbon and electrophilic at the carbonyl carbon. 

Until about 30 years ago, hydrazones derived from carbonyl compounds were not used in organic synthesis. They were used only for analytical purposes , and as protecting groups of aldehydes and ketones ". Corey investigated dimethylhydrazones of ketones and aldehydes with a-hydrogens, and found that they undergo deprotonation with LDA or BuLi in THF at the a-carbons to the hydrazonic moiety in 90-100% yield. The formed lithium compounds, used as enolate anion equivalents, create new carbon-carbon bonds in their reaction with different electrophiles such as alkyl halides or oxiranes, ketones and aldehydes (equation 21). 

Like the aldol and the Claisen, the Michael reaction also involves an enolate, so the mechanism begins with the deprotonation of an alpha carbon. In the Michael reaction, however, the electrophile is not an ordinary carbonyl, but an a,P-unsaturated carbonyl. Attack of the stable enolate nucleophile occurs at the beta carbon of the a,P-unsaturated carbonyl (called a 1,4-addition or conjugate addition or even Michael addition) to give an enolate intermediate. Protonation at the alpha carbon of the enolate gives the final product, a 1,5-dicarbonyl compound. 

Now we have created a powerfully addic species, the protonated carbonyl compound. Removal of a deuteron from the oxygen simply reverses the reaction to regenerate acetaldehyde and D30, but deprotonation at the a carbon generates the enol (Fig. 19.14). Note that the product is not an anionic enolate, but the neutral enol. If this enol regenerates the carbonyl compound in 030", exchanged acetaldehyde will result. 

The sixth chapter of the book was devoted to advances in enantioselective nickel-catalysed a-functionalisation, and to a-alkylation/arylation reactions of carbonyl compounds. A prochiral carbonyl compound can be activated toward electrophilic substitution via the formation of an enol or enolate intermediate, generating a tertiary or quaternary centre at the a-carbon. The use of a non-carbon electrophile leads to heterofunctionalised products, while that of carbon electrophiles affords a-arylated/alkylated carbonyl compounds, and the generation of a new stereogenic centre in these reactions... 

Enamines resemble enols because both have an increased electron density at a structurally related a carbon atom. The electron density at the a carbon atom in enamines is greater than that in enols because nitrogen is less electronegative than oxygen and releases an electron pair more readily. As a result, enamines are more nucleophilic than enols, and they are useful intermediates in alkylation reactions. We recall that enolate anions react with alkyl halides to give a-alkylated carbonyl compounds (Section 23.6), but uncharged enols are not sufficiently nucleophilic to be alkylated. Alkylation of the more nucleophilic enamine produces an iminium ion. 

The two preceding ChemActivities focused on reactions of carbonyl compounds that occur at the carbonyl carbon. This ChemActivity is the first in a series of three that focus on reactions at the alpha carbon. The common theme in all the alpha carbon ChemActivities is that the alpha carbon is nucleophilic, both in basic conditions (via an enolate) and in acidic conditions (via an enol). 

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... 

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