Base-Promoted Hydrolysis of an Ester

Base-promoted hydrolysis of an ester. Originally used to describe the hydrolysis of fats to make soap. (p. 1206)... 

Q I Mechanism 22.9 Base-Promoted Hydrolysis of an Ester to a Carboxylic Acid... 

The carboxylate ion is very unreactive toward nucleophilic substitution because it is negatively charged. Base-promoted hydrolysis of an ester, as a result, is an essentially irreversible reaction. 

The mechanism for base-promoted hydrolysis of an ester also involves a nucleophilic addition—elimination at the acyl carbon. 

Acid-Catalyzed Esterification 790 Base-Promoted Hydrolysis of an Ester 793 DCC-Promoted Amide Synthesis 798 Acidic Hydrolysis of an Amide 799 Basic Hydrolysis of an Amide 799 Acidic Hydrolysis of a Nitrile 801 Basic Hydrolysis of a Nitrile 801... 

Fischer Esterification—Acid-Catalyzed Conversion of Carboxylic Acids to Esters 848 Conversion of Carboxylic Acids to Amides with DCC 850 Acid-Catalyzed Hydrolysis of an Ester to a Carboxyhc Acid 851 Base-Promoted Hydrolysis of an Ester to a Carboxyhc Acid 852 Amide Hydrolysis in Base 856 Hydrolysis of a Nitrile in Base 864 Reduction of a Nitrile with LiAlH4 865 Reduction of a Nitrile with DIBAL-H 866... 

Differential Solvation of Reactants and Transition States. It should always be kept in mind that solvent effects can modify the energy of both the reactants and the transition state. It is the difference in the solvation that is the basis for changes in activation energies and reaction rates. Thus, although it is common to discuss solvent effects solely in terms of reactant solvation or transition state solvation, this is an oversimplification. A case that illustrates this point is the base-promoted hydrolysis of esters by hydroxide ion. 

The mechanism involves a Michael reaction followed by a Dieckmann reaction (intramolecular Claisen), all base promoted. Loss of the ester group begins with an add-catalyzed hydrolysis, followed by decarboxylation of the resulting carboxylic acid. Finally, a Robinson annulation with methyl vinyl ketone affords the final product. 

The hydrolysis of an ester in the presence of hydroxide ion is called a hydroxide-ion-promoted reaction rather than a base-catalyzed reaction because hydroxide ion increases the rate of the first step of the reaction by being a better nucleophile than water— not by being a stronger base than water—and because hydroxide ion is consumed in the overall reaction. To be a catalyst, a species must not be changed by or consumed in the reaction. Therefore, hydroxide ion is actually a reagent rather than a catalyst, so it is more accurate to call the reaction a hydroxide-ion-promoted reaction than a hydroxide-ion-catalyzed reaction. 

Somewhat similar effects are seen in the copper(II)-promoted hydrolysis of O-acetyl-2-pyridinecarboxaldoxime (47) (equation 20).215 In this case, water attack and hydroxide ion attack are accelerated by 1.1x10 and 2.2 xlO7 times respectively. Detailed analysis indicates that Cuu-bound water or hydroxide reacts with the carbonyl carbon of the ester as shown in (48). Promotion includes contributions from increases in the effective nucleophile concentration in addition to an enhancement in the leaving group ability. General base catalysis in the attack of coordinated water is also observed. 

The reaction typically gives 60% to 70% of the maximum yield. The reaction is a reversible process. An ester reacting with water, giving the carboxylic acid and alcohol, is called hydrolysis it is acid catalyzed. The base-promoted decomposition of esters yields an alcohol and a salt of the carboxylic acid this process is called saponification. 

Base-promoted hydrolysis is called saponification, from the Latin word sapo, for soap (see Section 23.2C). Refluxing an ester with aqueous sodium hydroxide, for example, produces an alcohol and the sodium salt of the acid ... 

As in the case of base catalysed hydrolysis, substituents in the aromatic ring influence the rate of hydrolysis of benzoyl esters. Halogens in the ortho- or meta- positions promote rapid hydrolysis while an amino group para to the ester results in relatively slow hydrolysis. Thus, for example, chloroprocaine is a shorter-acting version of procaine since its rate of hydrolysis by plasma esterases is about four times that of procaine. 

Acid-Catalyzed Hydrolysis. In acid-catalyzed ester hydrolysis the species that undergoes the rate-determining step is the protonated ester (Fig. 13.10). When the molecule is in this protonated form, the enhanced depletion of electrons near the central carbon promotes the approach of an electron-rich oxygen of a water molecule. Hence, the hydrolysis rate depends on the fraction of compound molecules that are protonated. This fraction, in turn, depends on how strong a base the ester function is. If we define an acidity constant (see Chapter 8) for the protonated species... 

The examples discussed above constitute a selection of recent applications of the acid and basic hydrolysis of (3-lactams in synthesis. Hydrolysis and alcoholysis of (3-lactams can also be effected under roughly neutral reaction conditions when enzymes are the promoters [47]. The (3-lactamases catalyzed hydrolysis of (3-lactams is an efficient process for a broad spectrum of substrates, including those (3-lactams with base or acid sensitive groups [12-14]. This process proceeds through an acyl enzyme intermediate to give ring opened (3-amino acids. The class C (3-lactamases in particular, in Scheme 9, have the ability to catalyze the alcoholysis reaction and hence (3-amino esters are the products formed. 

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