Esters base-mediated hydrolysis

Saponification is the base-mediated hydrolysis of an ester, yielding its component carboxylate salt and alcohol. Ammonolysis of esters gives amides. Esters react with Grignard reagents to give tertiary alcohols. With lithium aluminum hydride, on the other hand, they are reduced to primary alcohols. 

The hydrolysis is generally not carried out at pH 7 but is either acid-catalyzed or base-mediated (i.e., as a so-called saponification). Base-catalyzed ester hydrolyses do not exist The carboxylic acid produced protonates a full equivalent of base and thus consumes it. 

Base-mediated ester hydrolyses have a high driving force. This is because of the acid/base reaction between the carboxylic acid formed in the reaction, and the base used as the reagent. The resonance stabilization of the carboxylate is approximately 30 kcal/mol, which means a gain of about 16 kcal/mol compared to the starting material, the carboxylic ester (resonance stabilization 14 kcal/mol according to Table 6.1). Accordingly, the hydrolysis equilibrium lies completely on the side of the carboxylate. 

Swem oxidation is shown in Problem 3(d) of this chapter, the mechanism for the Homer-Emmons reaction is shown in Problem 2(c) of this chapter, and the mechanism for base-mediated ester hydrolysis was highlighted in Scheme 7.19. 

Pandey and coworkers developed an AgF-mediated route to azomethine yhdes starting from JV,A/-bis(trimethylsilylmethyl)alkyl amines and appHed this method of dipole formation toward a formal total synthesis of the Amar-yUidaceae class of alkaloids. Exposure of 176 to AgF effected a double desilylation and oxidation to furnish a transient azomethine yhde dipole (Scheme 37) (2011EJO4571). Cycloaddition of the dipole to the proximal enone fashioned tetracycle 177 in 56% yield. A base-mediated hydrolysis of the benzoyl ester occurred with concomitant epimerization, giving 178... 

Ester hydrolysis, an important organic reaction that is also of great biological importance, may be either acid- or base-catalyzed. The base-mediated process may be represented as follows ... 

Mechanism of Base-Mediated Ester Hydrolysis Step 1. Addition-elimination... 

Step 3. This step is a simple base-mediated ester hydrolysis (Section 20-4). 

Thiol 8 was reacted with tosylate 25 in any of several solvents led to acid 9 (after base mediated ester hydrolysis) in 75-85% yield. Bromomethyl ester 28 also reacted smoothly with 8, producing acid 9 in 70-75% yield after in situ base mediated hydrolysis (figure 7). 

These supported cycloadducts were then treated with a base (LiOH, NaOH) in a mixture of water and alcohol to give the expected free acid derivatives. However, while the latter compounds were readily recovered, the same was not true for the ionic liquid 4b, which was obtained as a dark brown liquid impure by NMR analysis. Very likely, the basic hydrolysis of the ester function caused the deprotonation of the imidazolium ring leading to a series of undesired side-reactions. Therefore, milder reaction conditions were explored to cleave the Diels-Alder product from the ionic liquid support. Handy and Okello found that the best method was the cyanide-mediated transesterification that gave the corresponding methyl esters 9-11 and allowed recover of 4b in at least 90% yield. It was also demonstrated that the recovered 4b could be used for further supported syntheses. In fact, in two subsequent mns the yields of the final ester compound were similar, indicating that the ionic liquid 4b could be efficiently recycled. 

A related reaction is the addition of isonitriles 75 to aldehydes 1 (the Passerini reaction). Denmark has demonstrated that SiCU, upon activation by a chiral Lewis base, which increased the Lewis acidity of the silicon (vide supra Scheme 7.14), can mediate this reaction to produce a-hydroxy amides 77 after aqueous work-up (Scheme 7.16). Phosphoramide 60 was employed as the chiral Lewis-basic catalyst [74]. Modification of the procedure for hydrolysis of 76 gives rise to the corresponding methyl ester (rather than the amide 77) [74]. (For experimental details see Chapter 14.5.5). 

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