Carboxylic acid esters base-catalyzed hydrolysis

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. 

Amides undergo an acid- or base-catalyzed hydrolysis reaction with water in the same way that esters do. Just as an ester yields a carboxylic acid and an alcohol, an amide yields a carboxylic acid and an amine (or ammonia). The net effect is a substitution of -N by -OH. This hydrolysis of amides is the key process that occurs in the stomach during digestion of proteins. 

Esters are subject to general acid or base-catalyzed hydrolysis to form a carboxylic acid and an alcohol. Both are equilibrium reactions and readily occur when equilibrium is shifted to the right. Base-catalyzed hydrolysis... 

The triethanolamine-catalyzed decarboxylation of l,3-dithiepane-2-carboxylic acid in DMSO <68T527i> as well as the acid- and base-catalyzed hydrolysis of the l,3-dithiepane-2-carboxylic acid ethyl ester have been studied <68T5293>. 

Acid and base-catalyzed hydrolysis of carboxylate esters usually proceeds OH... 

Before discussmg the mechanism of cleavage of carboxylic acid esters and amides by hydrolases, some chemical principles are worth recalling. The chemical hydrolysis of carboxylic acid derivatives can be catalyzed by acid or base, and, in both cases, the mechanisms involve addition-elimination via a tetrahedral intermediate. A general scheme of ester and amide hydrolysis is presented in Fig. 3. / the chemical mechanisms of ester hydrolysis will be... 

Fig. 3.1. General scheme for chemical hydrolysis of carboxylic acid esters and amides. Pathway a Proton (general acid) catalyzed hydrolysis. Pathway b HO (general base) catalyzed...

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. 8.4. Postulated mechanism of the base-catalyzed activation of (2-oxo-l, 3-dioxol-4-yl)methyl ester prodrugs (8.62) of carboxylic acids [74] [75]. After hydrolysis, the pro-moiety is liberated as a nonisolatable carbonate monoester intermediate, which is decarboxylated rapidly to a diketone.

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). 

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)... 

Figure 13.8 Variation of hydrolysis half-life at 25°C for several carboxylic acid esters as a function of solution pH due to changing contributions of the acid-catalyzed, neutral, and base-catalyzed mechanisms.

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 ... 

Neutral Hydrolysis. We finish our discussion of the major hydrolysis mechanisms of carboxylic acid esters by looking at the neutral (pH independent) reaction at the carbonyl carbon. From the reaction scheme given in Fig. 13.12, we see that, very similar to what we have postulated for the base-catalyzed reaction, the dissociation... 

When comparing the hydrolysis rate constants of a series of carboxylic acid esters (Table 13.8), it can be seen that the values for the acid-catalyzed reactions are all of the same magnitude, whereas the rate constants for the base-catalyzed reactions vary by several orders of magnitude. Explain these findings. 

Kinetic Considerations. Extensive kinetie and mechanistic studies have been made on the esterification of carboxylic acids since Berthclot and Saint-Gilles first studied the esterification of acetic acid. A number of mechanisms for acid- and base-catalyzed esterification have been proposed. One possible mechanism for the bimolecular acid-catalyzed ester hydrolysis and esterification is shown below. 

Problem-Solving Strategy Proposing Reaction Mechanisms 1007 Mechanism 21-8 Transesterification 1008 21-7 Hydrolysis of Carboxylic Acid Derivatives 1009 Mechanism 21-9 Saponification of an Ester 1010 Mechanism 21-10 Basic Hydrolysis of an Amide 1012 Mechanism 21-11 Acidic Hydrolysis of an Amide 1012 Mechanism 21-12 Base-Catalyzed Hydrolysis of a Nitrile 1014 21-8 Reduction of Acid Derivatives 1014... 

Nucleophilic reactions and general base-catalyzed hydrolysis of carboxylic acid derivatives behave kinetically in the same fashion the rate of disappearance of the carboxylic acid derivative or the rate of appearance of the alcohol moiety is first-order in nucleophile (or general base) and first-order in ester. For this reason these two grossly different types of reactions will be considered together. Detection of a nucleophilic reaction is sometimes difficult because the initial product of the reaction may very rapidly hydrolyze to carboxylic acid with the regeneration of the nucleophile. It is unsafe to assume that a direct reaction with the nueleopMle has taken place unless the products of the reaction can be shown to be derivatives of the nucleophile or imless, in the case where an unstable derivative is formed, detection of the intermediate by physical or chemical means is carried out. Such product determination studies cannot be neglected. 

Esters react by both acid and nucleophile initiated mechanisms. Hydrolysis of esters by acid catalysis is exactly the reverse of the mechanism for the acid-catalyzed esterification of a carboxylic acid. Base-catalyzed hydrolysis of esters is called saponification. Hydroxide attacks to form a tetrahedral intermediate. Loss of alkoxide ion then occurs. The alkoxide neutralizes the resulting carboxylic acid to form the salt. 

Regardless of whether the hydrolysis of a carboxylic acid ester occurs via the acid-catalyzed, neutral, or base-catalyzed mechanism, the products are the same that is, the compound is transformed to the corresponding acid and alcohol moiety ... 

Figure 4. Reaction scheme for the base-catalyzed hydrolysis of carboxylic acid esters.

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