Intramolecular catalysis in ester hydrolysis

Ester hydrolysis has been a very important system for the investigation of intramolecular catalysis. The types of displacements involved have been 

Bender and co-workers (Bender and Silver, 1962 Bender et ai, 1965) studied in detail the alkaline hydrolysis of methyl o-formylbenzoate [3], Variation 

Bowden and Taylor (1971b) have made a comprehensive survey of intramolcular catalysis of this type in the alkaline hydrolysis of 2-aroyl and 

2-acylbenzoates. Significant rate enhancements, above that expected for normal unassisted ester hydrolysis, occur for a number of methyl 2-acylbenzoates [16] as shown in Table 1. The rate ratios, relative to that 

These relations both demonstrate the inhibition of formation of the tetrahedral state which can be clearly attributed to steric crowding. Such a correlation as (5) confirms the attack at the neighbouring carbonyl group and this intramolecular catalysis for all this series. The activation parameters for the alkaline hydrolysis of these esters were also measured and are shown in Table 1. The enthalpies of activation of the 2-formyl, 2-acetyl, 2-propionyl, 2-isobutyryl and 2-pivaloyl esters are exceptionally small. These are 

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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... 

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. 

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... 

Intramolecular catalysis of ester hydrolysis by nitrogen nucleophiles is also important. The role of imidazole rings in intramolecular catalysis has received particularly close scruhny. There are two reasons for this. One is that the imidazole ring of... 

Each of the following molecules is capable of some form of intramolecular catalysis of ester hydrolysis. For each reactant, indicate one or more possible mechanisms for intramolecular catalysis. Indicate the relationship that you would expect to exist between the catalytic mechanism and the pH. Determine if that relationship is consistent with the experimental pH-rate profile shown in Fig. 7.P5. Depict a mechanism showing the proposed catalysis. 

There is also some evidence for intramolecular catalysis in the hydrolysis of mono-esters of 1,2-dihydroxy cyclopentane [48, 49, 50] and 3,4-dihydroxytetrahydrofuran [49] but the rate enhancements are small. Thus Irons-l-acetoxy-2-hydroxycyclopentane is hydrolysed 5.5 times more rapidly than trans-l-acetoxy-2-methoxy-cyclopentane and ds-1-acetoxy-2-hydroxycyclopentane is hydrolysed slightly more rapidly still (1.7 times). It has been suggested that these small rate enhancements do not arise from intramolecular catalysis but from a microscopic medium effect [49]. 

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). 

Yet another distinction is between intermolecular catalysis, in which the catalytic function and the reaction site are on different molecules, and intramolecular catalysis, in which the catalytic function and the reaction site are within the same molecule. All of the above examples constitute intermolecular catalyses. The following reaction, the hydrolysis of a monomaleate ester, is an intramolecular nucleophilic catalysis. 

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... 

At this juncture it is convenient to discuss the catalysis of ester hydrolysis by imidazole. The imidazolyl group of histidine is intimately involved in the mode of action of hydrolytic enzymes, and the two pathways believed to operate, general base catalysis and nucleophilic catalysis, were described in CHEC-I. In the latter, a 1-acetylimidazole is formed as an intermediate. General base catalysis has been proposed in the intramolecular thiolysis of A-propyl-2-thiomethylbenzamide... 

Breslow, R. and Mcallister, C, Intramolecular bifunctional catalysis of ester hydrolysis by metal ion and carboxylate in a carboxypeptidase model, J. Am. Chem. Soc., 1971, 93, 7096-7097. 

Intramolecular general-acid catalysis in the hydrolysis of phosphate and sulphate esters... 

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