Base-catalyzed ester hydrolysis

For the intermediates in base-catalyzed hydrolysis of a sulfate ester (10), pseudorotation about any of the equatorial bonds will necessarily put at least one in an apical position, which is strongly disfavored. ... 

Ester groups can be removed readily by base-catalyzed hydrolysis. When basic hydrolysis is inappropriate, special acyl groups are required. Trichloroethyl carbonate esters, for example, can be reductively removed with zinc.208... 

This property of organophosphate esters may be of environmental importance since phosphoric acid diesters are much more soluble and very little is known concerning the environmental toxicity of these compounds. The available data do not provide sufficient descriptions of the experimental methods to determine if the rates are reliable (Barnard et al. 1961 Ciba-Geigy 1984e, 1986 Howard and Deo 1979 Mayer et al. 1981 Wolfe 1980). The majority of reports provide only a minimum of information and exclude important facts such as the duration of the experiments and the concentration of buffers. Despite the lack of experimental detail, published rate constants for base-catalyzed hydrolysis appear to be reasonably consistent and suggest that the hydrolytic half-life of triphenyl phosphate will vary from... 

It is possible to reverse the formation of an ester by a catalyzed hydrolysis reaction. In this reaction, the water reenters the molecule where it was removed. If an acid is the catalyst, the original acid and alcohol will reform. If a base is the catalyst, the alcohol will reform however, the acid will react further to produce its conjugate base. The base-catalyzed hydrolysis of an ester is saponification. 

Base-catalyzed hydrolysis is employed primarily for the liberation of carboxyl groups protected as esters. The reaction involves direct attack by the hydroxide anion... 

FIGURE 3.9 Deprotection of carboxyl groups by base-catalyzed hydrolysis of (A) esters and (C) trifluoroacetamides, involving direct attack by the hydroxide anion. (B) tert-Butyl esters are resistant to saponification. 

Aquatic HS inhibited the base-catalyzed hydrolysis of the n-octyl ester of 2,4-D (i.e., 2,4-DOE). The hydrolysis rate of 2,4-DOE at pH 9-10 decreased by a factor equal to the fraction of the ester associated with the DHS. These observations are consistent with an unreactive humic-bound 2,4-DOE in equilibrium with reactive aqueous-phase 2,4-DOE. Thus, association between Dha and 2,4-DOE inhibited the base-catalyzed hydrolysis reaction. 

In HO -catalyzed hydrolysis (specific base catalyzed hydrolysis), the tetrahedral intermediate is formed by the addition of a nucleophilic HO ion (Fig. 3.1, Pathway b). This reaction is irreversible for both esters and amides, since the carboxylate ion formed is deprotonated in basic solution and, hence, is not receptive to attack by the nucleophilic alcohol, phenol, or amine. The reactivity of the carboxylic acid derivative toward a particular nucleophile depends on a) the relative electron-donating or -withdrawing power of the substituents on the carbonyl group, and b) the relative ability of the -OR or -NR R" moiety to act as a leaving group. Thus, electronegative substituents accelerate hydrolysis, and esters are more readily hydrolyzed than amides. 

Fig. 7.2. a) The most common mechanism of base-catalyzed ester hydrolysis, namely specific base catalysis (HCT catalysis) with tetrahedral intermediate and acyl cleavage. Not shown here are an W mechanism with alkyl cleavage observed with some tertiary alkyl esters, and an 5n2 mechanism with alkyl cleavage sometimes observed with primary alkyl esters, particularly methyl esters, b) Schematic mechanism of general base catalysis in ester hydrolysis. Intermolecular catalysis (bl) and intramolecular catalysis (b2). c) The base-catalyzed hydrolysis of esters is but a particular case of nucleophilic attack. Intermolecular (cl) and intramolecular (c2). d) Spontaneous (uncatalyzed) hydrolysis. This becomes possible when the R moiety is... 

The Hammett substituent constant o is a measure of the electron-with-drawing capacity of substituents directly conjugated to the reaction center [84], Since the values of this parameter were obtained from the rate constants of base-catalyzed hydrolysis of other aryl esters, it can be concluded from Eqn. 8.5 that the same electronic factors are involved in both cases. 

The saponification (the base-catalyzed hydrolysis of an ester) of fats has been important since ancient times. This process frees the glycerin and releases the fatty acids as carboxylate ions. The carboxylate ions, along with sodium or potassium ions from the base, create a soap (refer to Figure 16-28). 

The axial or equatorial nature of a substituent has a bearing on its reactivity, or ability to interact with its environment. Equatorial substituents are more stable and less reactive than their axial counterparts. For example, equatorial carboxyl groups are stronger acids than axial ones because of the higher stability of the carboxylate ion, whereas equatorial esters are hydrolyzed more slowly than axial ones because they are less accessible to protons or hydroxyl ions during acid- or base-catalyzed hydrolysis. 

Amides. Although similar to esters in terms of being a functional derivative of a carboxylic acid, amides, unlike esters, are relatively metabolically stable. In general, amides are stable to acid- and base-catalyzed hydrolysis. This stability is related to the overlapping electron clouds within the amide functionality and the corresponding multiple resonance forms. Amidases are enzymes that can catalyze the hydrolysis of amides. Nevertheless, amides are much more stable than esters. 

In discussing Reaction (F), we remarked that other anions are observed to compete with OH " in the Stern layer. This sort of electrolyte inhibition is widely observed, and the dependence of the inhibition on both the size and charge of the ions generally corresponds to expectations. For example, in the base-catalyzed hydrolysis of carboxylic esters in the cationic micelles, anions inhibit the reaction in the order N03 > Br " > Cl > F. For acid-catalyzed ester... 

Taft, following Ingold,39 assumed that for the hydrolysis of carboxylic esters, steric and resonance effects will be the same whether the hydrolysis is catalyzed by acid or base (see the discussion of ester-hydrolysis mechanisms, reaction 0-10). Rate differences would therefore be caused only by the field effects of R and R in RCOOR. This is presumably a good system to use for this purpose because the transition state for acid-catalyzed hydrolysis (7) has a greater positive charge (and is hence destabilized by - / and stabilized by + / substituents) than the starting ester, while the transition state for base-catalyzed hydrolysis (8)... 

Table 12.1 Reaction Rate Constants for the Base-Catalyzed Hydrolysis of Benzoic Acid Ethyl Ester (Ethyl Benzoate) in Various Organic Solvent-Water Mixturesa...

Before we turn to discussing neutral and base-catalyzed hydrolysis of ester functions, we need to reflect on what structural features determine how good a leaving... 

Figure 13.11 Reaction scheme for the base-catalyzed hydrolysis of carboxylic acid esters. + X a o V 1 of (fast) o—r2 ===== (fast) Ri-C. + HO—R2 0 (3)...

Base-Catalyzed Hydrolysis. Let us now look at the reaction of a carboxylic ester with OH", that is, the base-catalyzed hydrolysis. The reaction scheme for the most common reaction mechanism is given in Fig. 13.11. As indicated in reaction step 2, in contrast to the acid-catalyzed reaction (Fig. 13.10), the breakdown of the tetrahedral intermediate, I, may be kinetically important. Thus we write for the overall reaction rate ... 

In our first example we evaluate the influence of meta and para ring substituents on the base-catalyzed hydrolysis of substituted benzoic acid esters ... 

Figure 13.15 Effects of substituents on the base-catalyzed hydrolysis of benzoic acid ethyl esters in ethanoliwater (85 15) at 25°C. Relative reaction rates are correlated with Hammet Oj constants (data from Tinsley, 1979).

Kirsch et al. (1968) investigated the base-catalyzed hydrolysis of 24 meta- and para-disubstituted benzoic acid phenyl esters in acetonitrile/water (1 2) at 25°C ... 

Whereas the phosphetanium (Sect. 2.2) derivatives undergo base-catalyzed hydrolysis with essentially complete retention of configuration, the reaction with the related thietanium salts proceeds with complete inversion of configuration and can be described simply as a direct nucleophilic substitution 35. As far as the author is aware, no exchange evidence of the type er countered in the acid-catalyzed hydrolysis of ethylene phosphate, has been found for the cyclic sulfate esters. Consequently despite the geometrical similarities between the cyclic sulfates and phosphates and the related hybridization of the central atoms, the situation in which a finite pentacovalent intermediate sulfur species exists has not been delineated (restricting the discussion to esters). 

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