In our discussion of nucleophilic addition reactions we saw that primary amines react with aldehydes and ketones to produce imines. Equation 1 illustrates this transformation for the reaction of acetophenone with methyl amine.
In this reaction the initially formed tetrahedral intermediate, A, undergoes a typical reaction of alcohols, namely dehydration. As the color coding in Equation 1 indicates, loss of the OH group in A could be accompanied by loss of a proton from either the NH group or the CH3 group. The former alternative is preferred because the C-N double bond is more stable than the C-C double bond that would be produced via the latter route, i.e. the more stable product is preferred.
Note that the amine has to be primary, i.e. have two hydrogen atoms attached to the nitrogen, for this course of events to occur. As Equation 2 indicates, reaction of a secondary amine initially follows the same course as that of a primary amine, but now the tetrahedral intermediate, B, cannot form an imine because the nitrogen does not have a second hydrogen atom to lose:
Consequently, intermediate Bundergoes dehydration to form an alkene. (Note that the starting material must have at least one hydrogen attached to the a-carbon in order for this reaction to occur.) But this type of alkene is special. It is called an enamine. We will consider the special nature of enamines in a moment, but first let's think about the implications of the equilibrium arrows in Equations 1 and 2. There are two noteworthy points to be made here: 1. The formation of the product in high yield will be facilitated by removal of the water from the equilibrium mixture. This might be done by addition of a drying agent to the reaction, or by distillation of the water. 2. Imines and enamines may be converted into aldehydes and ketones by acid catalysed hydrolysis, i.e. by reaction with a large excess of water.
Enamines, Enols, and Enolate Ions
We have seen that ketones exist in solution in equilibrium with their enol tautomers. We have also seen that enolate ions exist as a resonance hybrid in which the negative charge resides primarily on the carbonyl oxygen and the a-carbon. The build up of electron density on the a-carbon makes this atom nucleophilic. Similar charge delocalization occurs in enamines as well. Figure 1 presents a comparison of the structural and chemical similarities between enols, enolates, and enamines.
The 3 Es
In all of these compounds a lone pair of electrons is conjugated to the pi system of the C-C double bond. This interaction lends nucleophilic character to the a-carbon atom as indicated by the resonance structures e1, e2, and e3, in which the a-carbons bear a formal negative charge. Note the structural similarity between e2 and e3; enamines may be regarded as synthetic equivalents of enolate ions. However, as we shall see, there are significant differences between these two types of nucleophilic reagents.
Exercise 1A Draw the structure of the enamine that would be formed in the following reaction:
Exercise 1B Draw the resonance contributor analogous to e2 in Figure 1:
Exercise 2A Draw the structure of the enamine that would be formed in the following reaction:
Exercise 2B Draw the resonance contributor analogous to e2 in Figure 1:
Exercise 3 Which would you expect to be more nucleophilic? an enolate ion an enamine
Before we examine the synthetic utility of enamines, we have to consider one additional aspect of their formation; in the case of unsymmetrical ketones, two enamines may be formed. Figure 2 illustrates the alternatives for the reaction of the cyclic secondary amine pyrrolidine with with 2-methylcyclohexanone.
The reaction produces a mixture of enamines in which the less substituted isomer predominates. Presumably a steric interaction between the methyl group of the cyclohexyl ring and the methylene group of the pyrollidine ring, shown by the red arrow in the figure, reduces the extent of conjugation between the lone pair of electrons on the nitrogen atom and the pi system of the double bond in the more substituted case.
Exercise 4 Is the reaction outlined in Figure 2kinetically controlled thermodynamically controlled kinetically and thermodynamically controlled ?
Exercise 5 Which carbon atom has higher electron density ? C-2 in the more substituted enamine C-6 in the less substituted enamine
Bearing in mind the limitations implied by the results shown in Figure 2, let's take a look at the reactions of enamines with electrophilic reagents.
Alkylation of Enamines
At the end of the introduction to this topic we made the point that enamines may be converted into aldehydes and ketones by acid catalysed hydrolysis, i.e. by reaction with a large excess of water. Bearing this in mind, Figure 3 presents a specific example of the 3-step process involved in the alkylation of aldehydes and ketones.
Putting It All Together
The first step involves the formation of the enamine. In this case benzene is used as a solvent and the water that is formed is removed by azeotropic distillation. Steps 2 and 3 proceed without isolation of any intermediates. Compare step 3 to the reverse of the reaction outlined in Equation 2.
Since enamines are inherently less reactive than their enolate ion analogs, it is necessary to treat them with highly reactive alkylating agents in order to effect a reaction. Equation 3 provides a representative example.
The a-bromoketone is extremely reactive towards nucleophiles because of the orbital overlap between the pi system of the carbonyl group and the p orbital that develops as the hybridization of the reaction center changes from sp3 to sp2 in order to accomodate the incoming nucleophile in the pentavalent transition state. Figure 4 illustrates this orbital overlap for reaction 3.
Although enamines are not as nucleophilic as their enolate ion equivalents, their relatively low reactivity makes them excellent partners for Michael additions. Thus, the enamine derived from 2-methylcyclohexanone reacts with acrylonitrile as shown in Equation 5.
By contrast, direct alkylation of 2-methylcyclohexanone with acrylonitrile yields the regiosiomer shown in Equation 6.
Michael addition of enamines to a,b-unsaturated ketones may be coupled with intramolecular aldol condensations to produce cyclic ketones. This sequence of reactions is an alternative approach to traditional Robinson annulations. Equation 7 provides an example.
Exercise 6 Draw the structure of the product expected from each of the following steps:
Exercise 7 Draw the structure of the product expected from each of the following steps: