Tetrahedral intermediate Fischer esterification

Section 2010 Ester hydrolysis can be catalyzed by acids and its mechanism (Figure 20 4) is the reverse of the mechanism for Fischer esterification The reaction proceeds via a tetrahedral intermediate... 

We have seen this theme before in Section 19.14 when we presented the mechanism of the Fischer esterification. As was the case then, formation of the tetrahedral intermediate is rate-determining. 

Both methods are successful since the formation of a tetrahedral intermediate about the ester carbonyl carbon, which is rate limiting in classical Fischer esterification , is avoided in the HERON reaction of hydrazines and 1-acyl-l-alkoxydiazenes. 

Know the meaning of Fischer esterification, nucleophilic addition-elimination (nucleophilic acyl substitution), tetrahedral intermediate, saponification, ammonolysis, acyl transfer. 

The mechanism for the Fischer esterification is shown in Figure 19.3. Sulfuric acid, hydrochloric acid, orp-toluenesulfonic acid is most often used as a catalyst. The mechanism will be easier to remember if you note the similarities to other acid-catalyzed mechanisms, such as the one for the formation of acetals in Figure 18.5. Also note that the steps leading from the tetrahedral intermediate to the carboxylic acid and alcohol starting materials and to the ester and water products are very similar. 

Nucleophilic acyl substitution also takes place in acid. Under acidic conditions, no strong nucleophile is present to attack the carbonyl group. The carbonyl group must become protonated, activating it toward nucleophilic acyl substitution. Attack by a weak nucleophile gives a tetrahedral intermediate. In most cases, the leaving group becomes protonated before it leaves, so it leaves as a neutral molecule. We now cover the Fischer esterification, a particularly useful example of an acid-catalyzed nucleophilic acyl substitution. 

Basic hydrolysis of esters, called saponification, avoids the equilibrium of the Fischer esterification. Hydroxide ion attacks the carbonyl group to give a tetrahedral intermediate. Expulsion of alkoxide ion gives the acid, and a fast proton transfer gives the carboxylate ion and the alcohol. This strongly exothermic proton transfer drives the saponification to completion. A full mole of base is consumed to deprotonate the acid. 

Carboxylic acids react with alcohols to form esters. The reaction must be carried out in an acidic solution, not only to catalyze the reaction but also to keep the carboxylic acid in its acid form so that it will react with the nucleophile. Because the tetrahedral intermediate formed in this reaction has two potential leaving groups of approximately the same basicity, the reaction must be carried out with excess alcohol to drive it toward products. Emil Fischer (Section 5.5) was the first to discover that an ester could be prepared by treating a carboxylic acid with excess alcohol in the presence of an acid catalyst, so the reaction is called a Fischer esterification. 

Which of the following is the tetrahedral carbonyl addition intermediate (TCAI) for the Fischer esterification of ethanol and benzoic acid ... 

Mechanism of the Fischer Esterification Reaction. The Fischer esterification proceeds by nucleophilic attack of the alcohol on the protonated carbonyl group of the carboxylic acid to form a tetrahedral intermediate. Collapse of the tetrahedral intermediate regenerates the carbonyl group and produces the ester and water. The overall sequence is outlined here ... 

The second and third steps in Fischer esterification are also completely analogous to parts of aldehyde or ketone chemistry. A molecule of alcohol acts as a nucleophile and adds to the carbonyl carbon of the protonated carbonyl group (Fig. 17.21). For a ketone, this addition is followed by deprotonation, and gives the hemiacetal for the acid, a somewhat more complicated intermediate with one more hydroxyl group is formed. In both reactions, however, a planar, hybridized carbon has been converted into an intermediate with a tetrahedral carbon, called the tetrahedral intermediate. 

The complete mechanism for Fischer esterification is shown in Figure 17.24. Note the symmetry of the process about the tetrahedral intermediate A. Note also the similarity of B and C, the intermediates on either side of A. In intermediate B, the OR is protonated. This pathway leads back to the starting carboxylic acid. In intermediate C, it is an OH that is protonated. This path leads to the ester. To the left of B and C are D and E, the two resonance-stabilized intermediates resulting from protonation of the acid or ester carbonyl. 

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