Carbonyl a-Substitution Reactions
Carbonyl compounds exist in equilibrium with a very small amount of a structural isomer, termed an enol. An enol is formed by abstraction of a proton from the a-carbon, delocalization of the electrons onto the carbonyl oxygen, and finally, protonation of the oxygen to give an alkene bonded to an alcohol (an enol!). It is important to note that this is a true equilibrium and the carbonyl compound and its enol are distinct different chemical species, not resonance forms. Since both proton abstraction and donation are required in the isomerization, keto-enol isomerization is catalyzed by both acids and bases.
In spite of their low equilibrium concentrations, enols and enolate anions are useful in organic chemistry because they can be used as nucleophiles to attack electrophilic centers such as Br2, alkyl halides, and other carbonyl carbons.
Bromination of an a-carbon is accomplished by reacting the carbonyl compound with bromine in an acidic solution (or in acetic acid as solvent). Under these conditions, the a-carbanion character of the enol attacks Br2 to form the a-bromo carbonyl compound, as shown below.
Chlorine can be introduced into the a-position conveniently using Cl2 in aqueous HCl.
The same general rules apply regarding enol stability as for alkenes, that is, the more highly substituted enol is favored, unless it is crowded sterically.
The a-halo ketones and aldehydes which are formed can undergo an E2 elimination reaction in the presence of base to give the a-b-unsaturated ketone or aldehyde; pyridine is commonly used as a base for this purpose.
a-b-Unsaturated ketones can also be prepared using an intermediate organo-selenium compound. Reaction of an enolizable carbon with LDA (lithium diisopropylamide; a very strong base prepared from diisopropylamine and butyllithium) generates the stable enolate anion as the lithium salt. This reacts with benzeneselenyl bromide to give the a-selenium intermediate, which is not isolated, but is oxidized with H2O2 to a powerful leaving group which eliminates to form the a-b-unsaturated ketone. The real beauty of this reaction is that it is useful for nitriles and esters, as well as ketones.
Direct bromination in acetic acid is limited to ketones and aldehydes, but a-bromo acids can be prepared using the Hell-Volhard-Zelinskii reaction. This reaction involves the conversion of the acid to the intermediate acid bromide, enolization, bromination to give the a-bromo acid bromide. The final step is work-up with water, which hydrolyzes the acid bromide to the acid, yielding the a-bromo acid as the final product. An interesting twist on this reaction is to work up the product in alcohol; this variation yields the corresponding a-bromo ester.
In another variation on the halogenation reaction, reaction of a methyl ketone or acetaldehyde (the only methyl aldehyde) with I2 in the presence of hydroxide anion generates the triiodo-ketone. Attack by hydroxide anion on this forms the corresponding carboxylic acid and iodoform, a yellow compound which is insoluble in the aqueous base. A precipitate of iodoform is a standard qualitative test for the presence of a methyl ketone.
