The Aac2 mechanism

The two unimolecular mechanisms for acid-catalyzed ester hycrolysis described above represent exceptional behaviour. They are generally observed only with compounds with narrowly defined structural characteristics, or under extreme conditions. The vast majority of esters are hydrolyzed under the vast majority of acidic conditions by the Aac2 mechanism, and since ester hydrolysis has been a traditional proving ground for theories relating structure and reactivity, a wealth of data is available. Yet the detailed mechanism of the reaction is still in dispute. 

This situation results from the combination of unfavourable circumstances summarized on pp. 57-58. The proper approach would seem to be to deal first with those areas which represent common ground between the various descriptions of the mechanism, before describing recent approaches towards a solution of the remaining problems. 

The first, and fundamental, piece of evidence necessary for a discussion of the detailed mechanism of any chemical change is the identification of the covalent bonds formed and broken this may or may not be the same thing as the identification of the products of the reaction. In the case of ester hydrolysis or formation the alternatives involve the cleavage or formation of bonds from oxygen to the carbon atom of either an alkyl or an acyl group, and it is in principle, and generally also in practice, a simple matter to distinguish between these alternatives. 

Since there are but two possibilities, acceptable evidence may be pos tive or negative. It is sufficient, for example, in order to establish acyl-oxygen fission, to show either that the acyl-oxygen bond is cleaved, or that the alkyl-oxygen bond is not, and both types of evidence have been used. Some of the evidence, for reactions involving alkyl-oxygen fission, has already been discussed in the sections dealing with the AA) 1 reaction (p. 87). 

Positive evidence that the acyl-oxygen bond is broken on ester hydrolysis and formation is available from experiments using H2,80. Hydrolysis in the enriched solvent results in a net incorporation of, sO into the carboxylic acid produced if acyl-oxygen cleavage occurs, viz- 

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It appears that the Aac2 mechanism gives a better agreement with experimental results than that of Goldschmidt. This is not in contradiction with the fact that the alcohol is more basic than the acid and that, consequently, the concentration of R OH is higher than that of RC(OH) since in any case a proton transfer from R OH to the acid is possible. 

For acid catalysis, matters are less clear. The reaction is generally second order, and it is known that amides are primarily protonated on the oxygen (Chapter 8, Ref. 24). Because of these facts it has been generally agreed that most acid-catalyzed amide hydrolysis takes place by the Aac2 mechanism. 

The transesterification and glycolysis reactions proceed via the Aac2 mechanism described above in Section 2.1. The reactions are acid catalyzed as demonstrated by Chegolya el al. [27], who added TPA to the polycondensation of PET and observed a significant increase of the apparent reaction rate. The industrial polycondensation process is accelerated by the use of metal catalysts, with these being mainly antimony compounds. 

Further evidence for this mechanism is that a small but detectable amount of 180 exchange (see p. 332) has been found in the acid-catalyzed hydrolysis of benzamide.551 (180 exchange has also been detected for the base-catalyzed process,562 in accord with the Bac2 mechanism). Kinetic data have shown that three molecules of water are involved in the ratedetermining step,563 suggesting that, as in the Aac2 mechanism for ester hydrolysis (0-10), additional water molecules take part in a process such as... 

With solutions of low acidity the increase in the concentration of the conjugate acid of the ester outweighs the decrease in activity of water, and the rate of hydrolysis by the A2 mechanism increases with increasing acid concentration, as expected. Most esters are, in fact, hydrolyzed by the Aac2 mechanism in less concentrated solutions of strong acids all the esters in Fig. 1, for ex-... 

Recently, Noyce and Pollack306 have found kinetic evidence for a changeover from acyl to alkyl-oxygen cleavage in the hydrolysis of a-acetoxystyrenes. At low acidities (1 M H2S04) compounds with electron-withdrawing substituents are hydrolyzed in a reaction which behaves as expected for the Aac2 mechanism. The solvent deuterium isotope effect, kH/kD = 0.75, and the effect of substituents on the rate is small. As the acidity of the medium is increased... 

A rather similar result has been obtained much more recently by Sadek et a/.108. These authors carried out a detailed investigation of the hydrolysis of benzyl acetate in aqueous dioxan, varying the solvent composition, and also the temperature (from 25 to 45°C). In the low-acidity region used (0.05 M HC1) the ester is hydrolyzed by the Aac2 mechanism, and the solvent effects are probably typical. The rate of hydrolysis decreases steadily as the proportion of dioxan in the medium is increased, as a result of a steady increase in AH, which is only partially offset by an increasingly favourable entropy of activation. However, the increase in AS1 eventually levels out at about 70% w/w dioxan, as illustrated by the data for 30°C ... 

If it is assumed that ester hydrolysis by the AAc2 mechanism involves fast pre-equilibrium protonation of the substrate, followed by rate-determining attack of water on the conjugate acid of the ester, the mechanism can be written as... 

The Aac2 mechanism (Figure 6.22) of ester hydrolysis represents an SN reaction at the carboxyl carbon, which follows the general mechanism of Figure 6.5. Acid-catalyzed hydrolyses of carboxyhc esters that are derived from primary or from secondary alcohols take place according to the Aac2 mechanism. The reverse reactions of these hydrolyses follow the same mechanism, namely, the acid-catalyzed esterifications of carboxylic acids with alcohols. In the esterifications, the same intermediates are formed as during hydrolysis, but in the opposite order. 

Fig. 6.22. Spontaneous lactonizations according to the Aac2 mechanism of Figure 6.19.

Solomon et al. [35] concluded that the observed high-order kinetics for esterification and polyesterification reactions ruled out unimolecular AacI AalI mechanisms, and that the Aac2 mechanism was the most likely. 

This mechanism (A = acid catalyzed, AC = acyl transfer, 1 = unimolecular) is observed in the esterification of 2,4,6-trisubstituted benzoic acids with R groups of moderate -i-M effect e.g. methyl). The Aac2 mechanism is blocked by the steric interference of the ortho substituents. Therefore, the acylium cation (17) is generated with anhydrous sulfuric acid and then treated with the alcohol (equation 2). R groups with strong -i-M effects, like methoxy, are not tolerable, as the aromatic nucleus undergoes sulfo-nation under the conditions. A variation of the AacI mechanism for aliphatic acids is achieved by using... 

In summary, the AAc2 mechanism is the commonest under acid conditions, with AAL1 occurring when R is able to form a stable carbonium ion while under basic conditions BAc2 operates in almost all cases. The other pathways only occur, if at all, in limited circumstances. 

Unlike acetals, for which one mechanism seems to describe most of the hydrolysis reactions that have been studied, the mechanism of acid-catalyzed hydrolysis of an ester depends on the structure of the ester and on the reaction conditions. For example, Yates concluded that hydrolysis of primary esters occurs by the Aac2 mechanism below 90% H2SO4 but changes to the AacI mechanism in solutions with higher concentrations of sulfuric acid (and... 

Hydrolyses with maximum curve (type I and II behavior) are easily explained by the Aac2 mechanism. The initial rate increase is attributed to the increasing concentration of the protonated ester. The rate then decreases since concentration of water required for the hydrolysis step decreases rapidly with increasing acid concentration (Scheme 8). The final rate increase suggests a transition to the A1 process (Aac 1 for type I esters and Aal 1 for type II esters). There is also a change in the mechanism for type III esters. Since the participation of vinyl and phenyl cations are unlikely, a change to the Aac 1 mechanism was suggested. Finally, the hydrolysis pathway for type IV esters is the AalI mechanism. 

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