Model carboxylic esters, hydrolysis

Because of the relative simplicity of carboxylic ester hydrolysis, in general, and that of base catalyzed ester hydrolysis, in particular, these reactions have served well as model systems in investigations of micellar effects on reaction rates and activation parameters. In addition, the prevalence in biological systems of carboxylic ester hydrolyses catalyzed by nucleophiles and by enzymes renders the investigation of micelle-catalyzed ester hydrolyses of obvious importance. 

If a reaction between neutral, dipolar molecules occurs with the formation of an activated complex with a dipole moment greater than either Rb> there will be an increase in the rate constant with increasing Sr according to Eq. (5-88). This is because a medium with higher Sr favours the production of any highly dipolar species as, in this case, the activated complex. In applying Eqs. (5-87) and (5-88) to experimental data, a model for the activated complex has to be constructed in order to evaluate reasonable values for and r. This has been done, for example, for the acid and base hydrolysis of carboxylic esters [11, 242]. 

M. Komiyama, M.L. Bender, M. Utaka, A. Takeda, Model for Charge-Relay Acceleration by Carboxylate Anion in Intramolecular General Base-Catalyzed Ester Hydrolysis by the Imidazolyl Group , Proc, Natl. Acad. Sci. USA, 74,2634 (1977)... 

This complex has been shown to be an excellent structural and functional model for the zinc hydrolytic enzymes, particularly carbonic anhydrase but also carboxypeptidase and the zinc phosphate esterases (24-26). The same complex also catalyzes the hydration of acetaldehyde and hydrolysis of carboxylic esters. These reactions appear to progress via a mechanism similar to that proposed for carbonic anhydrase. The rates are slower for [Zn([12]aneN3)OH] than for the enzyme but an order of magnitude faster than for existing model systems such as [(NH3)5Co(OH)]2+ (26). 

Pig Liver Esterase (PLE). This is the more used car-boxylesterase (carboxylic-ester hydrolase, EC 3.1.1.1, CAS 9016-18-6) which physiologically catalyzes the hydrolysis of carboxylic acid esters to the free acid anion and alcohol. PLE is a serine hydrolase which has been widely used for the preparation of chiral synthons and these applications have been fully reviewed. An active-site model for interpreting and predicting the specificity of the enzyme has been published. In the pioneering studies of the enzyme applications field, PLE was used for the chiral synthesis of mevalonolactone. Prochiral 3-substituted glutaric acid diesters... 

For example, a superb mimic of the charge-relay system in serine proteases has been prepared by attaching both carboxylate and imidazole to a-, fi-, and y-CyDs [24]. The hydroxy group, the last component of the charge-relay system, is provided by the CyDs. The activity (kinetic parameters) of the -CyD-based artificial enzyme for ester hydrolysis is close to that of aartificial enzymes show acylation, deacylation, and turnover, as is observed in the reactions of chymo-trypsin. The substrate-specificity is dependent on the kind of CyD used, since it is primarily governed by the substrate-binding process. In phenyl ester hydrolysis, a- and yS-CyD-based artificial enzymes are better than the y-CyD-based artificial enzyme. For the hydrolysis of tryptophan ethyl ester, however, the y-CyD-based artificial enzyme is the best. In another serine protease model, tripeptide (Ser-His-Asp) is directly introduced to the primary hydroxyl side of f -CyD [25]. This... 

Model studies of carboxypeptidase A are limited. It is found that some zinc complexes can hydrolyze the carboxylic ester, however, there is no suitable functional model that demonstrates the hydrolysis of normal carbox-amide by [Zn—OH]" species. 

The 8-parameter was used with good results in structure-activity correlations for modeling the acid-catalyzed carboxylic acid esterification and ester hydrolysis, and bimolecular substitution reactions (Chiriac et al. 1996). 

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. 

The presence of anhydride intermediates during the course of the hydrolysis of sulfite esters catalyzed by pepsin was proposed by May and Kaiser (14). Studies of the catalysis of sulfite ester hydrolysis by model carboxylate species indicated that the presence of anhydride intermediates could be detected in such reactions by the use of nucleophilic trapping reagents (17). Based on the results of the model studies, we were encouraged to attempt to trap the hypothetical anhydride intermediates formed in the pepsin-catalyzed hydrolysis of a sulfite ester using hydroxylamine as the trapping agent, which could lead to the identification of the active sites involved in this reaction. 

An ancient one is the production of soap from animal fat. To set that scene, 1 shall consider a simple model system, the hydrolysis (severing apart by water) of the two components of an ester, i (the same compound I used in Reaction 17, a combination of acetic acid and ethanol), and then turn to soapmaking itself You saw in Reaction 17 how esters can be broken down into their components, a carboxylic acid and an alcohol, by an acid here we see the analogous reaction in the presence of a base. To be specific, the reagent is a solution of sodium hydroxide, which provides the OH ions that catalyse the reaction. 

Carboxybiotin. The structure of biotin suggested that bicarbonate might be incorporated reversibly into its position 2. However, this proved not to be true and it remained for F. Lynen and associates to obtain a clue from a "model reaction." They showed that purified P-methylcrotonyl-CoA carboxylase promoted the carboxylation of free biotin with bicarbonate (H14C03 ) and ATP. While the carboxylated biotin was labile, treatment with diazomethane (Eq. 14-6) gave a stable dimethyl ester of N-l -carboxybiotin.53 54 The covalently bound biotin at active sites of enzymes was also successfully labeled with 14C02 Treatment of the labeled enzymes with diazomethane followed by hydrolysis with trypsin and pepsin gave authentic N-l -carboxybiocytin. It was now clear that the cleavage of ATP is required to couple the C02 from HCOs to the biotin to form carboxybiotin. The enzyme must... 

In models for carboxypeptidase A we showed the intracomplex catalyzed hydrolysis of an ester by a metal ion and a carboxylate ion [106], which are the catalytic groups of carboxypeptidase A. Some mechanistic proposals for the action of carboxypeptidase involve an anhydride intermediate that then hydrolyzes to the product and the regenerated enzyme. Although we later found convincing evidence that the enzyme does not use the anhydride mechanism in cleaving peptides [96-99], it may well use such a mechanism with esters. In a mimic of part of this mechanism we showed [107], but see also Ref. 108, that we could achieve very rapid hydrolysis of an anhydride by bound Zn2+, which is the metal ion in the enzyme. In another model, a carboxylate ion and a phenolic hydroxyl group, which are in the enzyme active site, could cooperatively catalyze the cleavage of an amide by the anhydride mechanism [109]. 

Lipases are the most frequently used enzymes in organic chemistry, catalyzing the hydrolysis of carboxylic acid esters or the reverse reaction in organic solvents [3,5,34,70]. The first example of directed evolution of an enantioselective enzyme according to the principle outlined in Fig. 11.2 concerns the hydrolytic kinetic resolution of the chiral ester 9 catalyzed by the bacterial lipase from Pseudomonas aeruginosa [8], This enzyme is composed of 285 amino acids [32]. It is an active catalyst for the model reaction, but enantioselectivity is poor (ee 5 % in favor of the (S)-acid 10 at about 50 % conversion) (Fig. 11.10) [71]. The selectivity factor E, which reflects the relative rate of the reactions of the (S)- and (R)-substrates, is only 1.1. 

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