Mechanism, tetrahedral ester hydrolysis

The most important species m the mechanism for ester hydrolysis is the tetrahe dral intermediate Evidence m support of the existence of the tetrahedral intermediate... 

This is like the A1 mechanism except that the protonated substrate SH +, instead of reacting alone, reacts with something else in the rate-determining step, a nucleophile or a base, written as Nu in equation (41). A typical example of this very common mechanism is ester hydrolysis, say of the methyl esters in equation (42), where SH+ reacts with two water molecules in the slow step,29 giving the neutral tetrahedral intermediate [5] directly. Reasonably enough, the rate equations obtainable are very similar to those for the A1 mechanism, with the addition of an extra aNu term, see equation (43) ... 

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. Mechanism of ester hydrolysis involves a high energy tetrahedral intermediate. Phos-...

The most important species in the mechanism for ester hydrolysis is the tetrahedral intermediate. Evidence in support of the existence of the tetrahedral intermediate was developed by Professor Myron Bender on the basis of isotopic labeling experiments he carried out at the University of Chicago. Bender prepared ethyl benzoate, labeled with the mass-18 isotope of oxygen at the carbonyl oxygen, then subjected it to acid-catalyzed hydrolysis in ordinary (unlabeled) water. He found that ethyl benzoate, recovered from the reaction before hydrolysis was complete, had lost a portion of its isotopic label. This observation is consistent only with the reversible formation of a tetrahedral intermediate under the reaction conditions ... 

Tertiary benzoyloxymethylsulfonamides (17) undergo hydrolysis via pH-independent and acid- and base-catalysed processes. Reactions are also buffer catalysed for buffer species with pXa values > 10.5. For the pH-independent pathway, hydrolysis takes place via formation of an Al-sulfonyliminium ion (Scheme 2). The mechanism of the acid-catalysed process involves pre-equilibrium protonation of the substrate followed by iminium ion formation. The base-catalysed pathway involves the normal Bac2 mechanism of ester hydrolysis. The buffer-catalysed reaction gives rise to a curved Brpnsted plot, with values of 1.6 and 0.25 for nucleophiles with pXa values <12.5 and >13, respectively. This is indicative of nucleophilic catalysis associated with a change in rate-limiting step from formation of the tetrahedral intermediate for buffer species with pXa > 13 to decomposition of the tetrahedral intermediate for buffer species with pXa < 12.5. ... 

Section 2010 Ester hydrolysis can be catalyzed by acids and its mechanism (Figure 20 4) is the reverse of the mechanism for Fischer esterification The reaction proceeds via a tetrahedral intermediate... 

Hydrolysis. Esters are cleaved (hydroly2ed) into an acid and an alcohol through the action of water. This hydrolysis is cataly2ed by acids or bases. The mechanistic aspects of ester hydrolysis have received considerable attention and have been reviewed (16). For most esters only two reaction pathways are important. Both mechanisms involve a tetrahedral intermediate and addition-elimination reactions i7i7... 

FIGURE 20.4 The mechanism of acid-catalyzed ester hydrolysis. Steps 1 through 3 show the formation of the tetrahedral intermediate. Dissociation of the tetrahedral intermediate is shown in steps 4 through 6. 

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 ... 

This is the same mechanism as that given above for esters, in equation (42). The difference between esters and amides is apparent from a comparison of the two tetrahedral intermediates [5] and [17], The former contains three oxygens, any of which can be protonated, resulting in much lsO exchange being observed when the reaction takes place in 180-enriched water,275,276 but [17] contains a much more basic nitrogen, which will be protonated preferentially and lead to much less 180 exchange, as observed.274 277,278 Also, ammonium ion formation makes the overall reaction irreversible, unlike ester hydrolysis. The calculated solvent isotope effect for the Scheme 15 process is 1.00,280 exactly in accord with experimental observation.278,279... 

The term acid catalysis is often taken to mean proton catalysis ( specific acid catalysis ) in contrast to general acid catalysis. In this sense, acid-catalyzed hydrolysis begins with protonation of the carbonyl O-atom, which renders the carbonyl C-atom more susceptible to nucleophilic attack. The reaction continues as depicted in Fig. 7. l.a (Pathway a) with hydration of the car-bonium ion to form a tetrahedral intermediate. This is followed by acyl cleavage (heterolytic cleavage of the acyl-0 bond). Pathway b presents an mechanism that can be observed in the presence of concentrated inorganic acids, but which appears irrelevant to hydrolysis under physiological conditions. The same is true for another mechanism of alkyl cleavage not shown in Fig. 7.Fa. All mechanisms of proton-catalyzed ester hydrolysis are reversible. 

Fig. 7.1. a) Specific acid catalysis (proton catalysis) with acyl cleavage in ester hydrolysis. Pathway a is the common mechanism involving a tetrahedral intermediate. Pathway b is SN1 mechanism observed in the presence of concentrated inorganic acids. Not shown here is a mechanism of alkyl cleavage, which can also be observed in the presence of concentrated inorganic acids, b) Schematic mechanism of general acid catalysis in ester hydrolysis. 

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... 

TETRAHEDRAL INTERMEDIATE ESTER HYDROLYSIS MECHANISM CHYMOTRYPSIN SERPINS (Inhibitory Mechanism)... 

Under acidic conditions, the mechanism of amide hydrolysis resembles the acid-catalyzed hydrolysis of an ester. Protonation of the carbonyl group activates it toward nucleophilic attack by water to give a tetrahedral intermediate. Protonation of the amino group enables it to leave as the amine. A fast exothermic proton transfer gives the acid and die protonated amine. 

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 ... 

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