Carboxylic esters, hydrolysis tetrahedral mechanism

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 ... 

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 ... 

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 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 ... 

Fig. 6.3. Alkaline hydrolysis of carboxylic esters according to the mechanism of Figure 6.2 proof of the reversibility of the formation of the tetrahedral intermediate. In the alkaline hydrolysis of ethyl pora-methylbenzoate in H20, for example, the ratio kretlo/kelj is at least 0.13 (but certainly not much more).

Fig. 6.3. Alkaline hydrolysis of carboxylic esters according to the mechanism of Figure 6.2 proof of the reversibility of the formation of the tetrahedral intermediate.

Section 19.10 Ester hydrolysis in basic solution is called saponification and proceeds through the same tetrahedral intermediate (Mechanism 19.4) as in acid-catalyzed hydrolysis. Unlike acid-catalyzed hydrolysis, saponification is irreversible because the carboxylic acid is deprotonated under the reaction conditions. 

Esters are less reactive than acid chlorides and anhydrides in addition reactions, but more reactive than amides. Esters can be converted into their parent carboxylic acids under either basic or acidic aqueous conditions in a process called, logically enough, ester hydrolysis. In base, the mechanism is the familiar addition-elimination one (Fig. 18.31). Hydroxide ion attacks the carbonyl group to form a tetrahedral intermediate. Loss of alkoxide then gives the acid, which is rapidly deproto-nated to the carboxylate anion in basic solution. Notice that this reaction, saponification (p. 862), is not catalytic. The hydroxide ion used up in the reaction is not regenerated at the end. To get the carboxylic acid itself, a final acidification step is necessary. 

The basic hydrolysis mechanism (shown next for a primary amide) is similar to that for hydrolysis of an ester. Hydroxide attacks the carbonyl to give a tetrahedral intermediate. Expulsion of an amide ion gives a carboxylic acid, which is quickly deproto-nated to give the salt of the acid and ammonia. 

Using the chiral ester X as a starting material, draw the carboxylate anion and alcohol formed (including stereochemistry) from hydrolysis of X via the accepted mechanism (having a tetrahedral intermediate) and the one-step Sn2 alternative. Given that only one alcohol, (R)-2-butanol, Is formed in this reaction, what does this indicate about the mechanism ... 

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. 

Fig. 2. Schematic diagram of the catalytic mechanism of 20S proteasomes. A proton transfer from the hydroxyl group of Thrl of /3 subunits to its own terminal amino group initiates the nucleophilic attack (I). As a result of the nucleophilic addition to the carbonyl carbon of the scissile peptide bond, a tetrahedral intermediate is formed (II). By an N—O acyl rearrangement, an ester is formed (the acyl enzyme) and the amino-terminal cleavage product is released (III). Finally, hydrolysis of the acyl enzyme yields the carboxyl-terminal cleavage product and frees the enzyme for another reaction cycle (IV).

The cr value alone can, of course, be used to understand the mechanism of those reactions which do not come under the ambit of cj+ and u values. For instance, the base hydrolysis of a benzoic acid ester may take two different pathways (a) nucleophilic attack of hydroxide ion on the carbonyl carbon to result in a tetrahedral intermediate, in a rate determining step, followed by its collapse into carboxylic acid or (b) nucleophilic attack of hydroxide ion on the alkyl carbon of the ester function, leading to the formation of the carboxylate directly. Since the carbonyl carbon is closest to the ring, the effect of a substituent felt by it must be much larger than the effect felt by the alkyl carbon. Hence, the rate of hydrolysis will be expected to increase much more in the former instance than in the latter with the increase in the substituent s a value. This is indeed the case as evident from the a versus rate constant k given in Table 3. The large increase in the rate of hydrolysis with the increase in cr could be justified only if the tetrahedral pathway is involved. The correlation of cr with log k is linear as seen from the plot in Fig. 5. 

Esters with tertiary alkyl groups undergo hydrolysis much more rapidly than do other esters because they hydrolyze by a completely different mechanism—one that does not involve formation of a tetrahedral intermediate. The hydrolysis of an ester with a tertiary alkyl group is an SnI reaction because when the carboxylic acid leaves, it leaves behind a relatively stable tertiary carbocation. 

The cobalt(III)-promoted hydrolysis of amino acid esters and peptides and the application of cobalt(III) complexes to the synthesis of small peptides has been reviewed. The ability of a metal ion to cooperate with various inter- and intramolecular acids and bases and promote amide hydrolysis has been investigated. The cobalt complexes (5-10) were prepared as potential substrates for amide hydrolysis. Phenolic and carboxylic functional groups were placed within the vicinity of cobalt(III) chelated amides, to provide models for zinc-containing peptidases such as carboxypeplidase A. The incorporation of a phenol group as in (5) and (6) enhanced the rate of base hydrolysis of the amide function by a factor of 10 -fold above that due to the metal alone. Intramolecular catalysis by the carboxyl group in the complexes (5) and (8) was not observed. The results are interpreted in terms of a bifunctional mechanism for tetrahedral intermediate breakdown by phenol. 

In base the tetrahedral intermediate is formed in a manner analogous to that proposed for ester saponification. Steps 1 and 2 in Mechanism 19.7 show the formation of the tetrahedral intermediate in the basic hydrolysis of amides. In step 3 the basic amino group of the tetrahedral intermediate abstracts a proton from water, and in step 4 the derived ammonium ion dissociates. Conversion of the carboxylic acid to its corresponding carboxylate anion in step 5 completes the process and renders the overall reaction irreversible. 

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