Ester rate constant of hydrolysis

The hydrolysis of a-amino acid esters in the pH region 7-8 is negligible, but in the presence of metal ions such as Co(II), Cu(II), Mn(II), Ca(II), and Mg(II), rapid hydrolysis occurs and the rate of hydrolysis increases with increasing metal ester ratio until a maximum value is reached when the metal ester ratio is 1 1 (122). It can therefore be concluded that the rate-determining step is the hydrolysis of the 1 1 species. The reaction was found to be independent of buffer concentration but quite sensitive to pH changes. An increase in the hydroxide ion concentration by a factor of ten caused a fourfold increase in the rate constant of hydrolysis. It is unlikely that this increase in the rate constant is caused by the increased concentration of hydroxide ions which participate in a second-order reaction with the... 

Table 12.6 Approximate value of the pseudo zero-order rate constant of hydrolysis for ester-containing polymers...

The importance of the free amino group in the process also comes across when comparing the rate constants of hydrolysis of phenyl benzoate and phenyl 2-aminobenzoate 1 in the same pH 4-8.5 range. As depicted in Fig. 23.2, the hydrolysis of phenyl benzoate is considerably slower than that of 1. As both esters only differ by the presence of the amino group in the aromatic ring, the differences in reaction rates again point to the involvement of the amino group in the reaction. 

More recently, Kaiser and coworkers reported enantiomeric specificity in the reaction of cyclohexaamylose with 3-carboxy-2,2,5,5-tetramethyl-pyrrolidin-l-oxy m-nitrophenyl ester (1), a spin label useful for identifying enzyme-substrate interactions (Flohr et al., 1971). In this case, the catalytic mechanism is identical to the scheme derived for the reactions of the cycloamyloses with phenyl acetates. In fact, the covalent intermediate, an acyl-cyclohexaamylose, was isolated. Maximal rate constants for appearance of m-nitrophenol at pH 8.62 (fc2), rate constants for hydrolysis of the covalent intermediate (fc3), and substrate binding constants (Kd) for the two enantiomers are presented in Table VIII. Significantly, specificity appears in the rates of acylation (fc2) rather than in either the strength of binding or the rate of deacylation. 

Having a weak O—O bond, peroxides split easily into free radicals. In addition to homolytic reactions, peroxides can participate in heterolytic reactions also, for example, they can undergo hydrolysis under the catalytic action of acids. Both homolytic and heterolytic reactions can occur simultaneously. For example, perbenzoates decompose into free radicals and simultaneously isomerize to ester [11]. The para-substituent slightly influences the rate constants of homolytic splitting of perester. The rate constant of heterolytic isomerization, by contrast, strongly depends on the nature of the para-substituent. Polar solvent accelerates the heterolytic isomerization. Isomerization reaction was proposed to proceed through the cyclic transition state [11]. 

Quantitative measurements of simple and enzyme-catalyzed reaction rates were under way by the 1850s. In that year Wilhelmy derived first order equations for acid-catalyzed hydrolysis of sucrose which he could follow by the inversion of rotation of plane polarized light. Berthellot (1862) derived second-order equations for the rates of ester formation and, shortly after, Harcourt observed that rates of reaction doubled for each 10 °C rise in temperature. Guldberg and Waage (1864-67) demonstrated that the equilibrium of the reaction was affected by the concentration ) of the reacting substance(s). By 1877 Arrhenius had derived the definition of the equilbrium constant for a reaction from the rate constants of the forward and backward reactions. Ostwald in 1884 showed that sucrose and ester hydrolyses were affected by H+ concentration (pH). 

Other 4-nitrophenyl esters have also been reported to be substrates of various hydrolases. For example, 4-nitrophenyl hexanoate (7.19) was hydrolyzed by bovine serum albumin [39], The affinity of the substrate for the macromolecule was found to be high (Km/n = 0.040 mM, where n is the number of sites), but the reaction itself was slow ( = 5 10-3 s-1, where k2 is the first-order rate constant of the formation of the phenol product from the enzyme-substrate complex). Another ester, 4-nitrophenyl pivalate (7.20), was hydrolyzed by cytoplasmic aldehyde dehydrogenase at a maximum velocity ca. 1/3 and an affinity ca. 1/20 those of the acetate [40], However, the rate-limiting steps were different for the two substrates, namely acylation of the enzyme for the pivalate, and acyl-enzyme hydrolysis for the acetate (see Chapt. 3). 

The Hammett substituent constant o is a measure of the electron-with-drawing capacity of substituents directly conjugated to the reaction center [84], Since the values of this parameter were obtained from the rate constants of base-catalyzed hydrolysis of other aryl esters, it can be concluded from Eqn. 8.5 that the same electronic factors are involved in both cases. 

Similarly, chemical hydrolysis of a number of a-amino acyl prodrugs of metronidazole (8.100, R=H see Sect. 8.5.4) was compared to the serum-catalyzed reaction [135][136]. The amino acids used for esterification included alanine, glycine, isoleucine, leucine, lysine, phenylalanine, and valine. Under physiological conditions of pH and temperature, ty2 values for hydrolysis in human serum ranged from 4.5 min for the Phe ester to 96 h for the lie ester. A good linear relationship was established between the log of the rate constant of enzymatic hydrolysis and the log of the rate constant of HO-cata-... 

Thus for aspirin, which has a rate constant of 0.0133 h for the hydrolysis of its ester group at 25° and pH 7.0, the half-life can be calculated as follows ... 

In 1984 Gassman and Granrud, and Novak and co-workers, published their results on reactions of similar esters of hydroxamic acids. Gassman and Granrud showed that the rearrangement of the methanesulfonate esters 45a-g in CDCI3 (Scheme 23) occurred in a first-order fashion and that kobs correlated with with a slope,, of -9.2. Novak and co-workers showed that the pH-independent first-order rate constants for hydrolysis in 5 vol%... 

The enhanced reactivity in the cupric ion-catalyzed hydrolysis cannot be due solely to the electrostatic effect of an attack of hydroxyl ion on a positively charged a -amino ester, since the introduction of a positive charge, two atoms from the carbonyl group of an ester, increases the rate constant of alkaline hydrolysis by a factor of 103 (10), whereas there is a difference of approximately 106 between the cupric ion-catalyzed and the alkaline hydrolyses of DL-phenylalanine ethyl ester. The effective charge on the cupric ion-glycine (buffer)-ester complex is +1, so that the factor of 106 cannot be explained by an increase in charge over that present in the case of betaine. Furthermore, the reaction cannot be due to attack by a water molecule on a positively charged a-amino acid ester, since the rate constant of the acidic hydrolysis of phenylalanine ethyl ester is very small. It thus seems... 

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