Enolate anions, carboxylic acids, reaction

The sites of alkylation are the oxygen atoms of the hydroxyl, carbonyl, and carboxyl groups in lignin. Reactions a and b are selective with diazoalkanes (a) reacting under anhydrous conditions to alkylate, chiefly, the slightly acidic hydroxyl groups (98) of the phenolic, enolic(99-102), and carboxylic (103-107) units to form ethers. The diazoalkane reaction with carboxylic acids only occurs in solvents in which the acid is deprotonated to an enolate anion. The RN reactions are shown in Equation 2. 

An enolate anion generated from a carboxylic acid derivative may be used in the same sorts of nucleophilic reactions that we have seen with aldehyde and ketone systems. It should be noted, however, that the base used to generate the enolate anion must be chosen carefully. If sodium hydroxide were used, then hydrolysis of the carboxylic derivative to the acid (see Section 7.9.2) would compete with enolate anion formation. However, the problem is avoided by using the same base, e.g. ethoxide, as is present in the ester... 

Alkylation of the a-position of suitable carboxylic acid derivatives may be achieved using the enolate anion as nucleophile in a typical Sn2 reaction (compare Section 10.2). In the example shown, the... 

Nucleophilic addition of an enolate anion from a carboxylic acid derivative onto an aldehyde or ketone is simply an aldol-type reaction (see Section 10.3). 

Now this is exactly the same situation we encountered when we compared the reactivity of aldehydes and ketones with that of carboxylic acid derivatives (see Section 7.8). The net result here is acylation of the nucleophile, and in the case of acylation of enolate anions, the reaction is termed a Claisen reaction. It is important not to consider aldol and Claisen reactions separately, but to appreciate that the initial addition is the same, and differences in products merely result from the absence or presence... 

To participate in this sort of reaction, the carboxylic acid derivative acting as nucleophile must have a-hydrogens in order to generate an enolate anion. In practice, esters are most commonly employed in Claisen-type reactions. 

The nucleophile in biological Claisen reactions that effectively adds on acetyl-CoA is almost always malonyl-CoA. This is synthesized from acetyl-CoA by a reaction that utilizes a biotin-enzyme complex to incorporate carbon dioxide into the molecule (see Section 15.9). This has now flanked the a-protons with two carbonyl groups, and increases their acidity. The enzymic Claisen reaction now proceeds, but, during the reaction, the added carboxyl is lost as carbon dioxide. Having done its job, it is immediately removed. In contrast to the chemical analogy, a carboxylated intermediate is not formed. Mechanistically, one could perhaps write a concerted decarboxylation-nucleophilic attack, as shown. An alternative rationalization is that decarboxylation of the malonyl ester is used by the enzyme to effectively generate the acetyl enolate anion without the requirement for a strong base. 

This problem covers a reaction sequence and a variety of different reactions, some easier than others. This one includes enolate anions, electrophilic cyclization, nucleophilic substitution, and simple carboxylic acid chemistry. 

Enolate hydroxylation is a problem of long standing. Direct oxygenation succeeds with the fully substituted enolates of certain a,a-disubstituted ketones and a variety of carboxylic acid derivatives (ester anions, acid dianions, amide anions), but the reaction of enolates, RCH = C(0 )R or CH2 = C(0 )R, with oxygen results in complex products of overoxidation. The stable... 

The anions of esters such as ethyl 3-oxobutanoate and diethyl propanedioate can be alkylated with alkyl halides. These reactions are important for the synthesis of carboxylic acids and ketones and are similar in character to the alkylation of ketones discussed previously (Section 17-4A). The ester is converted by a strong base to the enolate anion, Equation 18-18, which then is alkylated in an SN2 reaction with the alkyl halide, Equation 18-19. Usually, C-alkylation predominates ... 

The conversion of acetyl-CoA into malonyl-CoA increases the acidity of the a-hydrogens, and thus provides a better nucleophile for the Claisen condensation. In the biosynthetic sequence, no acy-lated malonic acid derivatives are produced, and no label from [14C]bicarbonate is incorporated, so the carboxyl group introduced into malonyl-CoA is simultaneously lost by a decarboxylation reaction during the Claisen condensation (Figure 3.1). Accordingly, the carboxylation step helps to activate the a-carbon and facilitate Claisen condensation, and the carboxyl is immediately removed on completion of this task. An alternative rationalization is that decarboxylation of the malonyl ester is used to generate the acetyl enolate anion without any requirement for a strong base. 

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