Carboxylate ester, hydrolysis mechanisms

Taft, following Ingold," 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 10-10). 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 —I and stabilized by +1 substituents) than the starting ester. 

The use of a lipophilic zinc(II) macrocycle complex, 1-hexadecyl-1,4,7,10-tetraazacyclododecane, to catalyze hydrolysis of lipophilic esters, both phosphate and carboxy (425), links this Section to the previous Section. Here, and in studies of the catalysis of hydrolysis of 4-nitrophenyl acetate by the Zn2+ and Co2+ complexes of tris(4,5-di-n-propyl-2 -imidazolyl)phosphine (426) and of a phosphate triester, a phos-phonate diester, and O-isopropyl methylfluorophosphonate (Sarin) by [Cu(A(A(A/,-trimethyl-A/,-tetradecylethylenediamine)l (427), various micellar effects have been brought into play. Catalysis of carboxylic ester hydrolysis is more effectively catalyzed by A"-methylimidazole-functionalized gold nanoparticles than by micellar catalysis (428). Other reports on mechanisms of metal-assisted carboxy ester hydrolyses deal with copper(II) (429), zinc(II) (430,431), and palladium(II) (432). 

Fig. 5. Reaction mechanism for carboxyl ester hydrolysis by chymotrypsin.

Of the mechanisms of carboxylic ester hydrolysis, that for the base-catalyzed reaction is the best understood. It generally proceeds by bimolecular attack of hydroxide ion on the carbonyl group, forming a tetrahedral intermediate, followed by elimination with acyl-oxygen fission ... 

Again by analogy with peptide hydrolysis, metalloenzymes catalyzing ester hydrolysis may take advantage of additional chemical features provided by amino-acid residues present in the active-site cavity. This situation occurs with car-boxypeptidase, " which shows esterase activity in vitro. Although the rate-limiting steps for carboxylic esters and peptides may differ, several features, such as the pH dependences of cat and and the presence of two spectroscopically observable intermediates, point to substantially similar mechanisms. On the other hand, carboxylic ester hydrolysis catalyzed by carbonic anhydrase seems to rely on fewer additional features of the active-site cavity, perhaps only on the presence of a metal-coordinated hydroxide that can perform the nucleophilic attack on the carbonyl carbon atom." ... 

Day JNE, Ingold CK (1941) Mechanism and kinetics of carboxylic ester hydrolysis and carboxyl esterification. Trans Faraday Soc 37 686-705... 

The reaction of dimethylsulfoxonium methylide with enantiopure esters provided the corresponding carboxylic acids at room temperature without racemization. 0-labelled reagents showed that the reaction does not proceed through an ester hydrolysis mechanism. This methodology is general and can be considered a valid alternate route for ester cleavage when a substrate is sensitive to hydrolysis conditions. 

Perhaps the most extensively studied catalytic reaction in acpreous solutions is the metal-ion catalysed hydrolysis of carboxylate esters, phosphate esters , phosphate diesters, amides and nittiles". Inspired by hydrolytic metalloenzymes, a multitude of different metal-ion complexes have been prepared and analysed with respect to their hydrolytic activity. Unfortunately, the exact mechanism by which these complexes operate is not completely clarified. The most important role of the catalyst is coordination of a hydroxide ion that is acting as a nucleophile. The extent of activation of tire substrate througji coordination to the Lewis-acidic metal centre is still unclear and probably varies from one substrate to another. For monodentate substrates this interaction is not very efficient. Only a few quantitative studies have been published. Chan et al. reported an equilibrium constant for coordination of the amide carbonyl group of... 

The case of intramolecular participation in ester hydrolysis has been extensively studied using acetylsalicylic acid (aspirin) and its derivatives. The kinetic data show that the anion is hydrolyzed more rapidly than the neutral species, indicating that the carboxylate group becomes involved in the reaction in some way. Three mechanisms can be considered ... 

Most acid-catalyzed hydrolyses of carboxylic acid derivatives proceed by the A2 mechanism, as shown for ester hydrolysis ... 

Acid-catalyzed ester hydrolysis can occur by more than one mechanism, depending on the structure of the ester. The usual pathway, however, is just the reverse of a Fischer esterification reaction (Section 21.3). The ester is first activated toward nucleophilic attack by protonation of the carboxyl oxygen atom, and nucleophilic addition of water then occurs. Transfer of a proton and elimination of alcohol yields the carboxylic acid (Figure 21.8). Because this hydrolysis reaction is the reverse of a Fischer esterification reaction, Figure 21.8 is the reverse of Figure 21.4. 

Conversion of Amides into Carboxylic Acids Hydrolysis Amides undergo hydrolysis to yield carboxylic acids plus ammonia or an amine on heating in either aqueous acid or aqueous base. The conditions required for amide hydrolysis are more severe than those required for the hydrolysis of add chlorides or esters but the mechanisms are similar. Acidic hydrolysis reaction occurs by nucleophilic addition of water to the protonated amide, followed by transfer of a proton from oxygen to nitrogen to make the nitrogen a better leaving group and subsequent elimination. The steps are reversible, with the equilibrium shifted toward product by protonation of NH3 in the final step. 

Basic hydrolysis has been carried out on carboxylic esters labeled with O in the carbonyl group. If this reaction proceeded by the normal Sn2 mechanism, all the 0 would remain in the carbonyl group, even if, in an equilibrium process, some of the carboxylic acid formed went back to the starting material ... 

The intermediates 74 and 76 can now lose OR to give the acid (not shown in the equations given), or they can lose OH to regenerate the carboxylic ester. If 74 goes back to ester, the ester will still be labeled, but if 76 reverts to ester, the 0 will be lost. A test of the two possible mechanisms is to stop the reaction before completion and to analyze the recovered ester for 0. This is just what was done by Bender, who found that in alkaline hydrolysis of methyl, ethyl, and isopropyl benzoates, the esters had lost 0. A similar experiment carried out for acid-Catalyzed hydrolysis of ethyl benzoate showed that here too the ester lost However, alkaline hydrolysis of substimted benzyl benzoates showed no loss. This result does not necessarily mean that no tetrahedral intermediate is involved in this case. If 74 and 76 do not revert to ester, but go entirely to acid, no loss will be found even with a tetrahedral intermediate. In the case of benzyl benzoates this may very well be happening, because formation of the acid relieves steric strain. Another possibility is that 74 loses OR before it can become protonated to 75. Even the experiments that do show loss do not prove the existence of the tetrahedral intermediate, since it is possible that is lost by some independent process not leading to ester hydrolysis. To deal with this possibility. Bender and Heck measured the rate of loss in the hydrolysis of ethyl trifluorothioloacetate- 0 ... 

Of fhe eight mechanisms, seven have actually been observed in hydrolysis of carboxylic esters. The one that has not been observed is the BacI mechanism. 

The Mechanism of, and Constitutional Factors Controlling, the Hydrolysis of Carboxylic Esters. Pt. I. The Constitutional Significance of Hydrolytic Stability Maxima," JCS (1930) 10321057, on 1037. 

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... 

The occurrence of isotopic exchange of between water and carbonyl compounds has been observed to take place slowly with acetone (Cohn and Urey, 1938) and much more rapidly with acetaldehyde (Herbert and Lauder, 1938). This gives qualitative evidence for reversible hydration (since no other reasonable mechanism exists for isotopic exchange), but gives no quantitative information about the equilibrium position. Similarly, the fact that exchange occurs in the unhydrolysed ester during the hydrolysis of carboxylic esters (Bender, 1951) shows that the species RC(0H)20R is a stable intermediate rather than a transition state. 

The hydrolysis of an ester to alcohol and acid (1) and the esterification of a carboxylic acid with an alcohol (2) are shown here as an example of the Sn2 mechanism. Both reactions are made easier by the marked polarity of the C=0 double bond. In the form of ester hydrolysis shown here, a proton is removed from a water molecule by the catalytic effect of the base B. The resulting strongly nucleophilic OH ion attacks the positively charged carbonyl C of the ester (la), and an unstable sp -hybridized transition state is produced. From this, either water is eliminated (2b) and the ester re-forms, or the alcohol ROH is eliminated (1b) and the free acid results. In esterification (2), the same steps take place in reverse. 

Pharmacology Oseltamivir is an ethyl ester prodrug requiring ester hydrolysis for conversion to the active form, oseltamivir carboxylate. The proposed mechanism of action of oseltamivir is via inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release. 

The possibility that the reactions of derivatives of carboxylic acids might pass through tetrahedral intermediates (l) has long been considered (Lowry, 1926). In their important paper in which they classified the mechanisms of hydrolysis of carboxylic esters Day and Ingold (1941) wrote bimolecular... 

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... 

Klausen, J., M. A. Meier, and R. P. Schwarzenbach, Assessing the fate of organic contaminants in aquatic environments Mechanism and kinetics of hydrolysis of a carboxylic ester , J. Chem. Educ., 74, 1440-1444 (1997). 

The hydrolysis of the more reactive carboxylic esters is catalyzed by a wide range of oxyanions. The mechanism proposed for the neutral hydrolysis of esters on p. 158 involves two molecules of water, one as a nucleophile and one as a general base. In principle an oxyanion or other nucleophile can replace either of these molecules, and both general base and nucleophilic catalysis of ester hydrolysis are well-known. The detailed mechanism of nucleophilic catalysis depends, to some extent, on the type of anion concerned, but the differences occur at a relatively late stage in the reaction, and the similarities are sufficient to allow generalizations about oxyanion reactions as a class. Some of the differences are not normally kinetically significant, and are best mentioned briefly at this point. 

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. 

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