Enolates and Enols Help (page 2)
Carbonyl compounds, ketones, and aldehydes in particular, are in rapid equilibrium with an isomer in which a hydrogen has moved from the α -carbon to the oxygen. This new isomer, which is both an alkene and an alcohol, is known as an enol. The keto form is usually the most stable.
Structural isomers existing in rapid equilibrium are tautomers and the equilibrium reaction is tautomerism. The above is a keto-enol tautomerism.
Acidity of Hydrogens α to Carbonyl Groups. The carbon atoms immediately adjacent to a carbonyl group are called the α-carbons, and hydrogens on these carbons are acidic. The stability of the resulting anion is due to delocalization of the charge on to the oxygen atom. Acetone, for example, has a pKa of 20.
Treatment of ketones, aldehydes, esters, and amides (among other carbonyl-containing compounds) results in the formation of enolate anions. Since the carbanion-enolates are ambidentate (they have two different nucleophilic sites), they can be alkylated at carbon or at oxygen. Alkyl halides typically react preferably at carbon, while alkyl tosylates give larger amounts of O-alkylation.
Alkylation of Simple Enolates
Enolates are nucleophiles that react with alkyl halides (or sulfonates) by typical Sn2 reactions. Enolates are often formed using lithium diisopropylamide (LDA). This base is very strong and converts all the substrate to the anion. It is non-nucleophilic; it is too sterically hindered to react with RX.
Undesired di- and tri-alkylation can occur if the anion is not produced quantitatively. Ketones with H's on more than one α–carbon can give a mixture of alkylation products. Several different approaches have been developed to circumvent these problems.
Enamine Alkylations. Monoalkylation is readily accomplished using this method. Enamines are made from a ketone and a secondary amine (R2NH). Enamines of ketones are monoalkylated in good yield with reactive halides, such as benzyl and allyl. Enamines also can be acylated on the α–carbon with acid chlorides.
Alkylation Stable Enolates
The acidity of a hydrogen is greatly enhanced when the carbon to which it is attached is flanked by two carbonyl groups, as in diethyl malonate and ethyl acetoacetate. The anions formed from these compounds are stable and their reactivity is readily controlled.
Malonic Ester Synthesis of Substituted Acetic Acids. First, the enolate is formed with strong base (often NaOEt in EtOH), and the anion is alkylated by SN2 reactions with unhindered RX or ROTs.
Hydrolysis of the substituted malonic ester gives the malonic acid, which undergoes decarboxylation (loss of CO2) to form a substituted acetic acid.
Acetoacetic Ester Synthesis. As with the malonic ester procedure, either one or two alkyl groups can be introduced in the acetoacetic procedure. The overall procedure is the same as in the malonic ester synthesis, and clean monoalkylation (or dialkylation, if 2 alkylation steps are used) results.
Nucleophilic Addition to Conjugated Carbonyl Compounds: The Michael Reaction
α, β –Unsaturated carbonyl compounds can be attacked by nucleophiles at the β carbon, forming an enolate.
Protonation and tautomerization produces a β- alkylated carbonyl compound. These Michael additions, also known as conjugate additions, compete with addition to the carbonyl.
A condensation reaction leads to a product with a new C–C bond. Most often the new bond results from a nucleophilic addition of a reasonably stable carbanion-enolate to the C=O group (acceptor) of an aldehyde; less frequently the C=O group belongs to a ketone or acid derivative. Another acceptor is the C≡N group of a nitrile.
Aldol Condensation. The addition of an enolate to the C=O group of its parent compound is called an aldol condensation. The product is a β-hydroxycarbonyl compound. In a mixed aldol condensation, the enolate of an aldehyde or ketone adds to the C=O group of a molecule other than its parent.
Aldol condensations are reversible, and with ketones the equilibrium is unfavorable for the condensation product. To carry out condensations of ketones, the product is continuously removed from the basic catalyst. β-Hydroxycarbonyl compounds are readily dehydrated upon heating to give α, β-unsaturated carbonyl compounds.
Acylation of Enolates: The Claisen condensation. In a Claisen condensation, the enolate of an ester adds to the C=O group of its parent ester. The addition is followed by loss of the OR group of the ester to give an α, β-ketoester. In a mixed Claisen condensation, the enolate adds to the C=O group of a molecule other than its parent. The sequence of reactions is similar to the reactions discussed above. An enolate is formed, which then adds to the carbonyl of an ester.
Next, the carbonyl group reforms, accompanied by the expulsion of the –OR portion of the ester.
Each of these steps is reversible. The reaction is driven to completion by an irreversible step, in which a very stable enolate is formed. Acid is then added to protonate the enolate.
Practice problems for these concepts can be found at: Enolates and Enols Practice Problems
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