Forming an Enolate Ion

The amount of carbonyl compound converted to an enolate ion depends on the p a of the carbonyl compound and the particular base used to remove the a-hydrogen. 

For example, when hydroxide ion or an alkoxide ion is used to remove an a-hydrogen from cyclohexanone, only a small amount of the carbonyl compound is converted into the enolate ion because the product acid (H2O) is a stronger acid than the reactant acid (the ketone). (Recall that the equilibrium of an acid-base reaction favors dissociation of the strong acid and formation of the weak acid see Section 2.5.) 

In contrast, when LDA (lithium diisopropylamide) is used to remove the a-hydrogen, essentially all the carbonyl compound is converted to the enolate ion because the product acid (diisopropylamine, or DIA) is a much weaker acid than the reactant acid (the ketone). Therefore, we will see that LDA is the base of choice for those reactions that require the carbonyl compound to be completely converted to an enolate ion before it reacts with an electrophile (Section 18.7). 

LDA is easily prepared by adding butyllithium to diisopropylamine in THF at -78 °C (that is, at the temperature of a dry ice/acetone bath.) 

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I If one of the carbonyl partners contains no or hydrogens, and thus can t form an enolate ion to become a donor, but does contain an unhindered carbonyl group and so is a good acceptor of nucleophiles, then a mixed aldol reaction is likely to be successful. This is the case, for instance, when either benz-aldehyde or formaldehyde is used as one of the carbonyl partners. 

Neither benzaldehyde nor formaldehyde can form an enolate ion to add to another partner, yet both compounds have an unhindered carbonyl group. 

The mixed Claisen condensation of two different esters is similar to the mixed aldol condensation of two different aldehydes or ketones (Section 23.5). Mixed Claisen reactions are successful only when one of the two ester components has no a hydrogens and thus can t form an enolate ion. For example, ethyl benzoate and ethyl formate can t form enolate ions and thus can t serve as donors. They can, however, act as the electrophilic acceptor components in reactions with other ester anions to give mixed /3-keto ester products. 

From this we can conclude that two pKa values can be as much as eight units apart and AG will still be less than 50 kj / mol, low enough to permit rapid enzymatic reactions. However, for transfer of a proton from a C-H bond to a catalytic group, for example, to form an enolate ion for an aldol condensation (Chapter 13), the intrinsic barrier is known to be about 50 kj / mol.141 In this case, to allow rapid enzymatic reaction either the thermodynamic barrier must be very low, as a result of closely matching pKa values, or the enzyme must lower the intrinsic barrier. It may do both. 

In the former instance, the major structural condition is that one of the carbonyl components (either the aldehyde or the ketone) has no a-hydrogen and thus is unable to form an enolate ion, but is nevertheless sufficiently electrophilic at its carbonyl carbon that it reacts with the carbanion of the second carbonyl component. Examples are provided in the formation of 4-phenylbut-3-en-2-one from benzaldehyde (no a-hydrogens) and acetone in the presence of base, and the formation of benzylideneacetophenone from benzaldehyde and acetophenone (Expt 6.135). 

Enolate ions formed from, ketones or aldehydes are extremely important in the synthesis of more complex organic molecules. The ease with which an enolate ion is formed is related to the acidity of the a proton. The pKa of propane (acetone) is 19.3 that means that it is a stronger acid compared to ethane (pKa 60) and a much weaker acid than acetic acid (pKa 4.7), i.e. strong bases like sodium hydride, sodium amide, and lithium diisopropylamide LiN(i-C3H7)2 are needed to form an enolate ion. 

This reaction proceeds well because the benzaldehyde has no a-protons and cannot form an enolate ion. Therefore, there is no chance of benzaldehyde undergoing self-condensation. It can only act as the electrophile for another enolate ion. However, what is to stop the ethanal undergoing an Aldol addition with itself as already described. 

Mixed aldol condensations can be employed if one of the aldehydes has no hydrogens on the a-carbon, so it cannot form an enolate ion and can only act as the electrophilic partner in the reaction. Aromatic aldehydes are especially useful in this role because the dehydration product has additional stabilization from the conjugation of the newly formed CC double bond with the aromatic ring. This stabilization makes the equilibrium for the formation of this product more favorable. 

The base-catalyzed aldol involves the nucleophilic addition of an enolate ion to a carbonyl group. Step 1 A base removes an a proton to form an enolate ion. 

Step 1 A base removes an a proton to form an enolate ion. 

When the enolate of one aldehyde (or ketone) adds to the carbonyl group of a different aldehyde or ketone, the result is called a crossed aldol condensation. The compounds used Crossed Aldol in the reaction must be selected carefully, or a mixture of several products will be formed. Condensations Consider the aldol condensation between ethanal (acetaldehyde) and propanal shown below. Either of these reagents can form an enolate ion. Attack by the enolate of ethanal on propanal gives a product different from the one formed by attack of the enolate of propanal on ethanal. Also, self-condensations of ethanal and propanal continue to take place. Depending on the reaction conditions, various proportions of the four possible products result. 

A crossed aldol condensation can be effective if it is planned so that only one of the reactants can form an enolate ion and so that the other compound is more likely to react with the enolate. If only one of the reactants has an a hydrogen, only one enolate will be present in the solution. If the other reactant is present in excess or contains a particularly electrophilic carbonyl group, it is more likely to be attacked by the enolate ion. 

The abstraction of a-hydrogen in carbonyl compounds such as acetaldehyde by sodium hydroxide is a reversible reaction and forms an enolate ion that undergoes addition to the carbonyl carbon of another acetaldehyde molecule to give the aldol 3.13. This is called the aldol condensation " and its mechanism is shown in Scheme 3.6. 

Neither benzaldehyde nor formaldehyde can form an enolate ion to condense with itself or with another partner, yet both compounds have an unhindered and reactive carbonyl group. The ketone 2-methylcyclohexanone, for instance, reacts preferentially with benzaldehyde to give the mixed aidol product. 

Enolisation 1 involves the removal of the a-proton from a carbonyl compound to form an enolate ion 2. Homoenolisation involves the removal of a (i-proton 3 to form the homoenolate ion 4 or 5. Both the enolate and the homoenolate can be represented as carbanions, but whereas the enolate version 2b is merely a different way of representing a single delocalised structure, the homoenolate 5 is a different compound from the cyclopropane 4. No literal examples of homoenolates 5 are known so they have the status of synthons which may be represented in real life by reagents derived from cyclopropanols 4 among many other possibilities.1... 

The Michael addition involves conjugate nueleophilic addition of carbanions to olefins of the type C=C-Z [29], A base is used to form the carbanion by abstracting a proton from an activated methylene precursor (donor) which attacks the olefin (acceptor) (Scheme 4) forming an enolate ion which is stabilized by delocalization. Protonation of the enolate ion is mainly at the oxygen, which is more negative than the carbon, and this produces the enol, which tautomerizes. The mechanism is 1,4 nucleophilic addition (known as conjugate addition) to the C=C-C=0 (or similar) system, although the net result of the reaction is addition to carbon-carbon double bond. 

Two different esters can be used in the Claisen condensation as long as one of the esters has no a-protons and cannot form an enolate ion (Fig.V). P-Diketones can be synthesised from the mixed Claisen condensation of a ketone with an ester (Fig.W). It is better to use any ester that cannot form an enolate ion to avoid competing Claisen condensations. 

Crossed Claisen condensations are possible when one ester component has no a hydrogens and, therefore, is unable to form an enolate ion and undergo selfcondensation. 

Michael Addition. The Michael addition is a conjugate nucleophilic addition of a carbanion to electron-deficient olefins (Fig. 13) (54). A base is used to form the carbanion by abstraction of protons from activated methylene donors which attack the olefin acceptor forming an enolate ion. The mechanism is 1,4-addition of a nucleophile to the conjugated system. 

The second property of a carbonyl moiety is to increase the acidity of the a-hydrogen atoms, which are those on the carbon atoms directly attached to the carbonyl carbon atom. A result of the enhanced acidity of these a-hydrogens is that the a-carbon atoms can become nucleophilic either through deprotonation to form an enolate ion (Eq. 18.3), or by a keto-enol equilibration, called tau-tomerization, to give an enol (Eq. 18.4). As shown in Equation 18.3, an enolate, which is the resonance hybrid of the two contributing resonance structures 2a and 2b, can react with electrophiles, E, at an a-carbon atom to give net substitution of the electrophile for an a-hydrogen atom. A similar result attends the reaction of an enol 3 with an electrophile, E+ (Eq. 18.4). 

Deprotonation of an ct-hydrogen atom forms an enolate ion that is stabilised by resonance (Section 1.6.3)... 

Only one carbonyl partner can have a-hydrogens. This means that only one carbonyl partner can be deprotonated to form an enolate ion nucleophile. 

Figure 22.2 summarizes the relevant factors for choosing a base to form an enolate ion. The information summarized in this figure will be used several times in the upcoming sections of this chapter. 

The mechanism for an aldol condensation has two parts (Mechanism 22.6). The first part is just an aldol addition reaction, which has three mechanistic steps. The second part has two steps that accomplish the elimination of water. Normally, alcohols do not undergo dehydration in the presence of a strong base, but here, the presence of the carbonyl group enables the dehydration reaction to occur. The a position is first deprotonated to form an enolate ion, followed by expulsion of a hydroxide ion to produce a,p unsaturation. This two-step process, which is different from the elimination reactions we saw in Chapter 8, is called an Elcb mechanism. In an Elcb mechanism, the leaving group only leaves after deprotonation occurs. 

Hydroxide ion removes a proton from the a-carbon, forming an enolate ion. 

However, the bromine on the a-carbon of carboxylate ions can be replaced by basic nucleophiles, because carboxylate ions do not form enolate ions. Forming an enolate ion would require putting a second negative charge on the compound. 

It is important that a strong base such as LDA is used to form the enolate ion. If a weaker base such as hydroxide ion or an alkoxide ion is used, very little of the desired monoalkylated product will be obtained. We have seen that these weaker bases form only a small amount of enolate ion at equilibrium (Section 18.6). Therefore, after monoalkylation has occurred, there is still a lot of base present in solution, which can form an enolate ion from the monoalkyated ketone as well as from the unalkylated ketone. As a result, di-, tri-, and even tetra-alkylated products may be produced. 

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