Esters base-induced ester hydrolysis

Mechanism of base-induced ester hydrolysis (saponification). 

Acid-catalyzed hydrolysis of esters is the reverse of acid-catalyzed ester formation discussed previously. Base-induced ester hydrolysis (saponification) is an irreversible reaction. The initial step is the attack of hydroxide ion at the carbonyl carbon ... 

Exercise 18-23 a. Develop a mechanism for ester interchange between ethanol and methyl ethanoate catalyzed by alkoxide that is consistent with the mechanism of base-induced ester hydrolysis. 

In D we have the case of base-induced ester hydrolysis, a reaction known to occur via a tetrahedral intermediate. The transition state, which will resemble the tetrahedral intermediate, will have charge concentrated on the two oxygen atoms, and such a species is expected to be destabilized in a dipolar aprotic medium relative to the protic solvent. 

FIGURE 18.31 The base-induced ester hydrolysis reaction, saponification. 

Even though amides are the least reactive of the acyl compounds, they can nevertheless be hydrolyzed in either acid or base. The mechanisms of these reactions are directly related to those of acid- or base-induced ester hydrolysis. In base, the carbonyl carbon of an amide is attacked to give tetrahedral intermediate A (Fig. 18.39). 

There are certain difficulties in achieving this type of aldol reaction. First, alkali-induced ester hydrolysis would compete with addition. Second, a Claisen condensation of the ester might intervene, and third, the ester anion is a stronger base than the enolate anions of either aldehydes or ketones, which means reaction could be defeated by proton transfer of the type... 

Saponification (Section 21.6) An old term for the base-induced hydrolysis of an ester to yield a carboxylic acid salt. 

Any of these conditions constitutes an extremely stringent limitation, and there has always been some doubt expressed over the extent to which any one of them is indeed satisfied in reactions which nevertheless give quite good straight line Hammett plots thereby making the linear relationships that are observed all the more mysterious Examples are, however, known that can indeed be shown to conform to one or other of the above conditions. Thus for the base-induced hydrolysis of the esters (58),... 

The rate-limiting step is almost certainly attack of OH on the original ester (164). This is borne out by the activation parameters for the base-induced hydrolysis of MeC02Et AH° = 112kJmor ... 

Exercise 18-28 Explain why the base-induced hydrolysis of methyl 2,4,6-trimethyl-benzoate is unusually slow. Write a mechanism for the hydrolysis of methyl 2,4,6-trimethyl benzoate that occurs when the ester is dissolved in concentrated sulfuric acid and the solution poured into a mixture of ice and water (see Section 18-3A) ... 

An alternate route to substituted tetrahydrobenzazepines (Scheme 33) commenced with the Michael addition of the ester 351 to acrylonitrile in the presence of Triton B, and the intermediate cyanoester was converted to 352 by reduction of the ester function with lithium borohydride and O-benzylation (168). Base-induced hydrolysis of the nitrile group of 352 delivered the corresponding acid, which was transformed to 353 via a Curtius rearrangement. Subjection of 353 to a modified two-step Tschemiac-Einhom reaction involving AMiydroxymethyla-tion and subsequent acid-catalyzed cyclization gave 354. 

Table 6). Where the expense of tetra-n-butylammonium hydroxide is a consideration, or in cases where the product carboxylic acid is poorly soluble in ether (making extractive removal of tetra-n-butylammonium salts difficult), an alternative procedure employing sodium hydroxide in a mixture of water, methanol, and ferf-butyl alcohol can be used. The mechanism of the base-induced hydrolysis reaction is believed to involve initial rate-limiting intramolecular N- O acyl transfer, followed by rapid saponification of the resulting (3-amino ester. ... 

The reaction of sarin with hydrogen chloride has been reported and kinetics determined by NMR imaging (Bard et al., 1970). With rate constants determined at 25°C, 81.5°C, and 100°C, Arrhenius analysis led to a calculated activation energy of 17.8 kcal/mole. The base-induced hydrolysis of sarin analogs and tabun was studied by Larsson (1958b) and the half-life of GA has been estimated to be 1.5 min at pH = 11 at 25°C. Ultimately, and depending on conditions (pH, reaction times, and so forth), hydrolysis products may include fluoride ion (or hydrogen fluoride), the 1-methylethyl ester of methylphosphonic acid, methylphosphonic acid, and 2-propanol. 

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