Group Catalysis

A bell-shaped pH-rate constant profile is obtained in hydrolysis of 3-acetoxyphthalic acid [57] although bifunctional catalysis is not possible (Fersht and Kirby, 1968b). Kirby concludes that both carboxyl groups are involved in the reaction in a stepwise manner 

The pH-rate constant profile for hydrolysis of phthalamic acid showed participation by the undissociated carboxyl group, and an anhydride intermediate was detected (Bender, 1957 Bender et al., 1958b). Hydrolysis was 10s times faster than in the case of p-carboxybenzamide. A four-center mechanism [58] was postulated. 

The D20 solvent isotope effect for such a reaction should be large since proton transfer is occurring in the transition state, but the reaction is actually faster in D20 ( d2o/ h2o = 1 5)- As suggested by Bender, nucleophilic attack by the carboxylate ion on the proton-ated amide [equation (40)] may be the actual mechanism. Thus, the 

While a carboxylate anion is a potent nucleophile in an intramolecular reaction it is not powerful enough to displace methoxide or an unprotonated amine, unless the nucleophile and the carbonyl group are held even more rigidly than in the phthalate system. Kirby and Lancaster (referred to by Kirby and Fersht, 1971) have found that such displacement can occur in disubstituted maleate monoesters and amides. The estimated rate constant for cyclization of N-methyl dimethylmaleamic acid [equation (41)] is 16,000 times greater than that for the unsubstituted compound. Below pH 5-6 hydrolysis of the cyclic anhydride becomes rate-determining. 

An ionized carboxyl group can displace methoxide ion from methyl hydrogen diisopropyl maleate (Aldersley et al., 1972). There is a plateau in the pH-rate constant profile from pH 8-14 which was ascribed to reaction catalysed by the carboxylate anion [equation (42)]. 

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Imidazole Catalysis Hydroxyl Group Catalysis Mechanistic Conclusions... 

D. Piszkiewicz and T. C. Bruise, Glycoside hydrolysis. I. Acetamido and hydroxyl group catalysis in glycoside hydrolysis, J. Am. Chem. Soc., 89 (1967) 6237-6243. 

Bruice, T. C., T. H. Fife, J. J. Bruno, and N. E. Brandon, Hydroxyl group catalysis. II. The reactivity of the hydroxyl group to serine. The nucleophilicity of alcohols and the ease of hydrolysis of their acetyl esters nucleophilicity as related to their pK s , Biochemistry, 1,7-12 (1962). 

Although metal-promoted hydrolysis of phosphate esters is a topic of very current interest (Section 61.4.4), little work has been published dealing with the effects of metal ions on the hydrolysis of sulfate esters. The acid-catalyzed hydrolysis of aryl sulfates has been shown to occur by an A-l mechanism (Scheme 34).434 Nucleophilic catalysis by amines has been observed in the hydrolysis of p-nitrophenyl sulfate435 and intramolecular carboxyl group catalysis occurs with salicyl sulfate436 as with salicyl phosphate. 

Anderson, B. D., R. A. Conradi, and W. J. Lambert. 1984. Carboxyl group catalysis of acyl transfer reactions in corticosteroid 17- and 21-monoestefsPharm. Sci73 604-611. 

Intramolecular carboxyl group catalysis has been found in a number of salicyl acetals. Capon et al. (1969) preferred intramolecular general acid catalysis as the mechanism of carboxyl group participation in the hydrolysis of o-carboxyphenyl 3-D-glucoside and o-methoxymethoxybenzoic acid although the kinetically equivalent possibilities were not convincingly eliminated in the case of the glucoside. 

Fig. 33. The intramolecular neighboring hydroxyl group catalysis in hydrolysis of methyl cis-4-hydroxy-tetrahydroftiran-2.carboxylatc (122)...

Figure 3.19. A plot of the gel time of TGDDM resins of various levels of purity as a function of [OH]o as determined by MIR. The curve is calculated from a model of —OH group catalysis of epoxy ring-opening (St John et al., 1993).

Phosphate esters can be cleaved by template catalysts, especially those with cyclodextrin binding groups and linked catalytic groups. Catalysis of the hydrolysis of a bound cyclic phosphate by ribonuclease mimics has been extensively studied [92-98], as has catalysis by enzyme mimics carrying bound metal ions [99-102]. 

A new type of prodrug of d4T, 200, has been prepared. Such compounds, and the analogous ddT species, degrade hydrolytically under physiological conditions without the need for an enzyme. AZT and ddT derivatives 201 (R=Me, Ph) have also been prepared. Hydrolysis of the carboxylic ester leads to rapid release of the 5, 5 -dinucleosidyl phosphate by a process of neighbouring group catalysis, with a mixed phosphoric-carboxylic anhydride as an intermediate. ... 

Quaternary ammonium ion 36 terminal trimethylammonium groups, catalysis applications [257]... 

Dunn, B.M., Bruice, T.C. Further investigation of the neighboring carboxyl group catalysis of hydrolysis of methyl phenyl acetals of formaldehyde electrostatic and solvent effects. J. Am. Chem. Soc. 1970, 92(4), 6589-6594. 

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