Making Enolates

PROBLEMS Predict the products of each of the following reactions. Remember that you can only halogenate an alpha position that has protons. 

In the previous section, we saw that enols can be nucleophilic. But enols are only mUd nucleophiles. So, the question is how can we make the alpha position even more nucleophihc (so that we can have a broader range of possible reactions) There is a way to do this. We just need to give the alpha position a negative charge. To see how this can be achieved, let s quickly review the mechanism we saw for tautomerization under basic conditions, and let s focus on the intermediate (highlighted below)  

we expect both of these locations to be very nncleophilic. Nevertheless, we won t explore any reactions in which the oxygen atom fnnctions as a nncleophile (called O-attack). Most textbooks and instmctors do not teach the conditions for O-attack, becanse it is generally considered to be a more advanced topic. So, from now on, we will only explore examples of C-attack (where the alpha carbon acts as the nncleophile, attacking some electrophile)  

Notice that, in showing the attack, we have drawn only one resonance structnre of the enolate. If we had used the other resonance structure, it would have looked like this  

We will do it this way, because it will make the mechanisms easier to follow. To be absolutely correct, we should actually draw both resonance forms, like this  

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All the acid derivatives can form enols of some kind. Those of esters are particularly important and either enols or enolates are easily made. It is obviously necessary to avoid water in the presence of acid or base, as esters hydrolyse under these conditions. One solution is to use the alkoxide belonging to the ester (MeO- with a methyl ester, EtO- with an ethyl ester, and so on) to make enolate ions. 

Carbon-carbon bonds can also be made with alkyl boranes. The requirement for a carbon nucleophile that bears a suitable leaving group is met by a-halo carbonyl compounds. The halogen makes enolization of the carbonyl compound easier and then departs in the rearrangement step. The product is a boron enolate with the boron bound to carbon. Under the basic conditions of the reaction, hydrolysis to the corresponding carbonyl compound is rapid. 

CoA thiol esters are widely used in nature. Mostly they are acetyl CoA, but other thiol esters are also used to make enols. We will see more of this chemistry in the next chapter. The two enol equivalents that wc have met so far are quite general lysine enamines can be used for any aldehyde or ketone and CoA thiol esters for any ester. Another class of enol equivalent—the enol ester—has just one representative but it is a most important one. 

The electron-donating enol -OH groups make enols more reactive than alkenes. 

First steps in making enol(ate)s with regiochemical control. 

The Reformatsky reaction, in which an a-bromocarbonyl compound was treated with Zn to give an enolate, was for a very long time the only way of quantitatively making enolates of weakly acidic carbonyl compounds. Nowadays it has been superseded by strong nonnucleophilic bases like LDA and KHMDS. 

The idea of kinetic versus thermodynamic control can be illustrated by discussing briefly the formation of enolate anions from unsymmetrical ketones. A more complete discussion of this topic is given in Chapter 7 and in Part B, Chapter 1. Any ketone with more than one type of a-proton can give rise to at least two enolates when a proton is abstracted. Many studies, particularly those of House,have shown that the ratio of the two possible enolates depends on the reaction conditions. If the base is very strong, such as the triphenylmethyl anion, and there are no hydroxylic solvents present, enolate 6 is the major product. When equilibrium is established between 5 and 6 by making enolate formation reversible by using a hydroxylic solvent, however, the dominant enolate is 5. Thus, 6 is the product of kinetic control... 

Carboxylic acid derivatives can be created via FGIs, beginning with either a carboxylic acid or from another carboxylic acid derivative. Since it is possible to make enolates from esters, tertiary amides, and nitriles, these compounds can also be prepared by alkylation at the alpha carbon. 

Despite their charge distribution, enolate anions react as carbon nucleophiles that create new carbon-carbon bonds, making enolate anions important for organic synthesis. 

FIGURE 19.36 The initially formed a-iodo carbonyl compound is a stronger acid than the carbonyl compound itself. The introduced iodine makes enolate formation easier. 

This anion reacts in Sn2 fashion with iodine to generate the a-iodo carbonyl compound. Now, however, the electron-withdrawing inductive effect of iodine makes enolate formation easier, not harder, as for enols. The negative charge of the enolate is stabilized by the electron-withdrawing effect. A second and third displacement reaction on iodine generates the a,a,a-triiodo carbonyl compound (Fig. 19.37). Similar reactions are known for bromine and chlorine. 

In the previous section, we learned how to make enolates. Now, we will begin to see what an enolate can attack. In this section, we will explore the reaction between an enolate and a halogen (such as Br, Cl, or I). In the following sections, we will explore the reactions between an enolate and other electrophiles. 

So far in this chapter, we have learned how to make enolates, and we have used them to attack various electrophiles (including halogens and alkyl halides). In this section, we will explore what happens when an enolate attacks a ketone or aldehyde. 

In practice, the strong base lithium diisopropylamide [LiN(i-C3H7)2 abbreviated LDA] is commonly used for making enolate ions. As the lithium salt of the weak acid diisopropylamine, pl a = 36, LDA can readily deprotonate most carbonyl compounds. It is easily prepared by reaction of butyllithium with diisopropylamine and is soluble in organic solvents because of its two alkyl groups. 

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