Hydrolysis of Esters and Amides

Hydrolysis of esters and amides by enzymes that form acyl enzyme intermediates is similar in mechanism but different in rate-limiting steps. Whereas formation of the acyl enzyme intermediate is a rate-limiting step for amide hydrolysis, it is the deacylation step that determines the rate of ester hydrolysis. This difference allows elimination of the undesirable amidase activity that is responsible for secondary hydrolysis without affecting the rate of synthesis. Addition of an appropriate cosolvent such as acetonitrile, DMF, or dioxane can selectively eliminate undesirable amidase activity (128). 

A good example to illustrate the difference in the rates of hydrolysis of esters and amides is to compare the metabolism of procaine and procainamide because the only difference between the two drugs is that one is an ester and the other is an amide (Fig. 6.2). Procaine has a half-life of about 1 minute due to the rapid hydrolysis of the ester, whereas... 

FIGURE 6.3 Mechanism for esterase-catalyzed hydrolysis of esters and amides. 

P. Deslongchamps, Stereoelectronic Control in the Cleavage of Tetrahedral Intermediates in the Hydrolysis of Esters and Amides , Tetrahedron 1977, 31, 2463 - 2490 P. Deslongchamps, Stereoelectronic Effects in Organic Chemistry , Pergamon Press, Oxford, 1983. 

Neighbouring-group participation in the hydrolysis of esters and amides has been reviewed. The effects of urea, Na+ and Li+ on the intramolecular general-base-catalysed glycolysis of phenyl salicylate (217) in glycol-acetonitrile solvent at constant water concentration have been reported. ... 

Hydrolytic reactions. There are numerous different esterases responsible for the hydrolysis of esters and amides, and they occur in most species. However, the activity may vary considerably between species. For example, the insecticide malathion owes its selective toxicity to this difference. In mammals, the major route of metabolism is hydrolysis to the dicarboxylic acid, whereas in insects it is oxidation to malaoxon (Fig. 5.12). Malaoxon is a very potent cholinesterase inhibitor, and its insecticidal action is probably due to this property. The hydrolysis product has a low mammalian toxicity (see chap. 7). 

The hydrolysis of esters (and amides) by chymotrypsin satisfies these criteria. The hydrolysis of, say, acetyl-L-tryptophan p-i itrophenyl ester forms an acylen-/yme that reacts with various amines such as hydroxylamine, alaninamide, hydrazine, etc., and also with alcohols such as methanol, to give the hydroxamic acid, dipeptide, hydrazide, and methyl ester, respectively, of acetyl-L-tryptophan. The same acylenzyme is generated in the hydrolysis of the phenyl, methyl, ethyl, etc., esters of the amino acid (and also during the hydrolysis of amides). 

Three new macrocyclic ligands (187) when complexed with zinc(II) could promote ester hydrolysis and a kinetic study of the hydrolysis of 4-nitrophenyl acetate in Tris buffer at pH 8.63 in 10% (v/v) MeCN was earned out with these.153 The hydrolysis of lipophilic esters is also catalysed by zinc(H) in a complex of a long alkyl-pendant macrocyclic tetraamine (188) in micellar solution.154 A study with a copper chloride-containing micelle has compared its effectiveness in the hydrolysis of esters and amides.155... 

In a review of nucleophile isotope effects, results of studies of the hydrolysis of esters and amides by carboxypeptidase were discussed.10... 

Table 18.1 Comparison of hydrolysis of esters and amides for enzymes and antibodies.

In the basic hydrolysis of esters and amides, the formation of carboxylate ion is irreversible and so serves to drive the reaction to completion. 

H20 or OH Hydrolysis of esters and amides Ester hydrolysis (Section 6.4.1)... 

The trypsin family of serine proteases includes over 80 well-characterized enzymes having a minimum sequence homology of >21%. Two amino acid residues are absolutely conserved (Cysl82, Glyl96) within their active sites [26,27]. These proteases have similar catalytic mechanisms that lead to hydrolysis of ester and amide bonds. This occurs via an acyl transfer mechanism that utilizes proton donation by histidine to the newly formed alcohol or amine group, dissociation and formation of a covalent acyl-enzyme complex. 

Formation of the 1 1 complexes with zinc and cadmium has been studied in aqueous solution, and the complexes are more stable than the corresponding 1 1 adducts with bipy 245). Ternary mercury(II)-hydroxo-terpy complexes are active catalysts for hydrolysis of esters and amides 477). 

The hydrolysis of esters and amides easily proceeds with the help of mineral adds. Polymer acids are expected to be effident catal3rsts because of the high local density of protons around the pol3mier chain. 

In the 1950 s, ion exchai retins were extentively studied as catalysts of the add hydrolysis of esters and amides. The earliest report in this connection may be... 

Davies RR, Distefano MD. A semisynthetic metalloenzyme based on a protein cavity that catalyzes the enantioselective hydrolysis of ester and amide substrates. J. Am Chem. Soc. 1997 119 11643-11652. 

Oxidation of tdcoholx and aldehydes Other miscellaneous oxidative rc.U tions Redtielive Rettcllons Reduction of aldehydes and ketones Reduction of nim> luid azo cxsmptmnds Miscelluneous ledudive reactions Hydrolytic Reaetions Hydrolysis of esters and amides... 

The hydrolysis of esters and amides (including peptides) is important in medicinal chemistry (see Chapters 36 and 38). Here, two drugs are presented to illustrate these two chemical classes. (-)-Cocaine (5) has two ester groups whose hydrolysis (Figure 32.7a) is a route of detoxification, which accounts for as much as 90% of the dose in humans. Three human enzymes are now known to be involved in the hydrolysis of cocaine. One is the liver carboxylesterase hCE-1 which catalyzes the hydrolysis of the methyl ester group. As for the benzoyl ester goup, it is hydrolyzed by the liver carboxylesterase hCE-2 and serum cholinesterase. 

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