Enolates and Enols Help
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.
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