6.2.2.6 1,4-Addition Reaction

The organocopper reagents are much softer nucleophiles and when they are used as a nucleophile for an α,β-unsaturated carbonyl compound, it results in not a 1,2 addition but rather 1,4-addition (Scheme 1). This is explained by the thermodynamic control of the reaction. A hard nucleophile like organolithium reagents instead react under kinetic control.

Scheme 1

6.2.2.7 Aldol Reactions

This reaction also involves the attack of a nucleophile, but the nucleophile is a carbanion generated from an aldehyde or ketone. This evidently requires a base to abstract a proton from the carbonyl compound to generate the carbanion. The carbanion so generated may now attack another molecule of aldehyde or ketone to generate a β-hydroxy carbonyl compound which may be dehydrated under suitable conditions to generate an α,β-unsaturated carbonyl compound (Scheme 2). The reaction is almost complete for aldehydes but in case of even simple ketones, the reaction almost completely lies to the left. The reason for such an observation lies in the reversibility of the formation of the carbanion. In such cases, where the attack of the carbanion the carbonyl compound is slower than the reprotonation of the carbonyl compound, the product will be formed only in small amounts. The reaction can be made to proceed quantitatively, if one of the products is removed continuously thereby pulling the reaction to the right.

Scheme 2

The β-hydroxy compound so formed may undergo elimination in the presence of excess of base to generate an α,β-unsaturated carbonyl compound. The reaction is evidently dependent on both the concentration of the base and the β-hydroxy carbonyl compound and is found to proceed by E1cB pathway.
It is to be noted that this reaction is essentially a reaction involving the enolate ions. Since enol formation from an aldehyde or ketone is feasible even in acid solution, so this reaction can be carried out using an acid as a catalyst. The reaction now follows a completely different pathway and almost always leads to the formation of the dehydrated product. Here,  the carbonyl compound forms an equilibrium concentration of enol which then attacks the protonated form of the carbonyl compound to give the “aldol” which may undergo elimination by E1 pathway to give the α,β-unsaturated carbonyl compound (Scheme 3).

Scheme 3

A further complication may arise on subjecting unsymmetrical ketones to aldol reaction. Now, there are two potential enols/enolates that could be formed and hence a mixture of products will be obtained. These rules out any synthetic utility for such reaction. However, in certain ketones, one side may be blocked by group so that it can enolize in one specific direction. Some examples of such ketones are t-butyl ketones, acetophenone and its derivatives and lactones (Scheme 4).

Scheme 4