Catalysis in ester hydrolysis

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... 

Neuvonen H. Kinetics and mechanisms of reactions of pyridines and imidazole with phenyl acetates and trifluoroacetates in aqueous acetonitrile with low content of water nucleophilic and general base catalysis in ester hydrolysis. J Chem Soc Perkin Trans II 1987 266 159-67. 

Cooperative Nucleophilic and General-acid Catalysis in Ester Hydrolysis... 

Activation of Leaving Groups. When the alkoxy oxygen atom is bound to a metal ion, its leaving ability from electrophilic carbon centers is enhanced, leading to catalysis in ester hydrolysis as exemplified by D (37). 

Motomura, T., Inoue, K., Kobayashi, K., and Aoyama, Y. (1991) Transition-state stabilization via dynamic molecular recognition a concerted acid-base bifunctional catalysis in ester hydrolysis. Tetrahedron Lett. 32,4657-4760. 

The catalysis of ester hydrolysis by other groups within the ester molecule (intramolecular catalysis) has been extensively studied (17,18). These reactions are important because they simulate catalysis by en2ymes. Intramolecular catalysis of esters has been used as a model in dmg discovery efforts (19). 

The study of both carbonyl and carbon acid participation in ester hydrolysis has been used by Bowden and Last (1971) to evaluate certain of the factors suggested for important roles in enzymic catalysis. A first model concerns a comparison of the three formyl esters and shows that the proximity of the formyl to the ester group and internal strain increase in passing along the series, 1,2-benzoate, 1,8-naphthoate and 4,5-phenanthroate. The very large rate enhancements result from the proximity of the internal nucleophile once formed and from internal strain. Strain is increased or induced by the primary... 

The second relevant set of data is for the formation of the anhydride from substituted succinic acid derivatives. Equilibrium constants for the formation of the anhydride from the acid are available for the various methyl-substituted compounds (Table A.l) and the derived EM s are compared in Table 5 with those for intramolecular nucleophilic catalysis in the hydrolysis of half-esters... 

M. I. Page, D. Render, G. Bemath, Stereochemical Studies. Part 112. Geometrical Dependence of Intramolecular Catalysis in the Hydrolysis and Aminolysis of Aryl Esters , J. Chem. Soc., Perkin Trans. 2 1986, 867-871. 

Higuchi et al. (1971) reported an example of possible bifunctional catalysis in the hydrolysis of the monosuccinate ester of hexa-chlorophene [7]. The monoacetate ester hydrolyses 500 times faster than the diacetate below pH 8, and the monosuccinate hydrolyses... 

Hydrophobic attractive interactions between a polymer and a small-molecule reactant often occur in reactions carried out in aqueous media [Imanishi, 1979 Morawetz, 1975 Overber-ger and Guterl, 1978, 1979]. Acid catalysis of ester hydrolysis by polysulfonic acids is most... 

However, in these reactions it is likely that breakdown of the tetrahedral intermediate is at least partly rate determining so the general acid catalysis is probably associated with this step rather than with attack of the nucleophile on the carbonyl group. The only example of general acid catalysis of ester hydrolysis where the rate limiting step is probably nucleophilic attack on the carbonyl group appears to be the hydrolysis of tetra-O-methyl-D-glucono-... 

Evidence comes from comparative rate studies.216 Thus 71 was hydrolyzed about 105 times faster than benzamide (PhCONH2) at about the same concentration of hydrogen ions. That this enhancement of rate was not caused by the resonance or field effects of COOH (an electron-withdrawing group) was shown by the fact both o-nitrobenzamide and terephthal-amic acid (the para isomer of 71) were hydrolyzed more slowly than benzamide. Many other examples of neighboring-group participation at a carbonyl carbon have been reported.2 7 It is likely that nucleophilic catalysis is involved in enzyme catalysis of ester hydrolysis. 

This sensitivity to substitution of neutral hydrolysis means that the pH-independent reaction gradually becomes more important than the hydroxide reaction at the high pH end of the region, and becomes much more rapidly more important than acid-catalyzed hydrolysis at low pH. Thus from Fig. 13, the acid-catalyzed reaction can be seen to be significant for the hydrolysis of ethyl acetate between pH 4 and 5, and for phenyl acetate about pH 2 but for 2,4-dinitrophenyl acetate the acid-catalyzed reaction is not detectable at pH 1, and is presumably important only in relatively strong acid. It seems certain that this fast neutral hydrolysis is at any rate a partial explanation for the low efficiency of acid catalysis in the hydrolysis of very weakly basic esters, such as the trifluoroacetates and oxalates, in moderately concentrated acid (see p. 145). 

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. 

The broad outline of the mechanism of catalysis of ester hydrolysis by hydroxide ion is not in doubt. The reaction is well known to involve acyl-oxygen cleavage, and seems invariably to be of the second order, being first order in both ester and hydroxide anion. General base catalysis in the usual sense is not a possibility, the partial removal of a proton from water cannot generate a species more reactive than hydroxide ion, so direct nucleophilic attack must be involved. (However, if it is accepted that the high ionic nobility of the hydroxide ion in water is explained by a Grotthus-type mechanism... 

Curiously, the clue to the successful observation of general base and nucleophilic catalysis of ester hydrolysis appeared in the literature only a few months... 

The transition from nucleophilic to general base catalysis of ester hydrolysis has been demonstrated by Kirsch and Jencks300 for attack by imidazole on a series of acetate esters. Their data are given in Table 41, and include a figure for the catalysis by imidazole of the hydrolysis of ethyl acetate. This must... 

This reaction process is depicted in general terms in equation (34), and includes the category generalized in equation (35). The earliest example of this type of reaction appears to be the ready transesterification of uncomplexed ester groups shown in Scheme 39,133,134 which intramolecular participation forms a new chelate ring in the transition state. Since this discovery, numerous studies have been made on the intramolecular catalysis of ester hydrolysis by metal-complexed hydroxide... 

General base and nucleophilic catalysis of ester hydrolysis and related reactions, 5, 237 H2O-D2O Mixtures, protolytic processes in, 7, 259... 

A reaction exhibiting general acid catalysis, the ester hydrolysis (XXXVIII), has been discussed in Sect. 2.3. The present section deals with a classic reaction which is subject to both general acid and base catalysis in homogeneous media, the mutarotation of D-glucose. 

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