Rate constant profile

Fig. 5 (a) The pH versus log hydrolysis rate constant profile of idoxuridine at 60°C (solid line). The dashed lines indicate the individual contributions of each kinetic term, (b) pH versus log hydrolysis rate constant profile of acetylsalicylic acid (solid line). The dashed lines indicate the individual contribution of each kinetic term. Adapted from Refs. 105 and 106. 

Lactams undergo both acid- and base-catalyzed hydrolysis [79]. The pH vs. log(rate constant) profiles of penicillins are V-shaped with rate constants at a minimum of ca. pH 7, whereas, for cephalosporins, these plots are U-shaped with minimum rate constants in the pH range of 3-7. The basis for this difference is that penicillins undergo no significant uncatalyzed (pH-independent) reaction, while, in contrast, for cephalosporins, a significant degree of spontaneous, pH-independent reaction between pH 3 and 7 is often observed [80],... 

Belke et al. (1971) reported general base and general acid catalysis in cyclization of 2-hydroxymethylbenzamide [equation (18)]. However, with 2-hydroxymethyl-6-aminobenzamide strict general base catalysis by buffer bases is observed with a Bronsted coefficient of O 39 (Fife and Benjamin, unpublished data). In contrast with the unsubstituted amide, the Bronsted plot is nicely linear. An amino-group in the 6-position might assist decomposition of a tetrahedral intermediate as in [37a, b] or a kinetic equivalent. The pH-rate constant profile for spontaneous cyclization at zero buffer concentra-... 

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 10 times faster than in the case of p-carboxybenzamide. A four-center mechanism [58] was postulated. 

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)]. 

The pH-rate constant profile shown in Figure 5 was obtained for hydrolysis of (73) in 50% dioxane-water at 15°. A large plateau in the profile is to be noted. As in the other cases of intramolecular catalysis, kinetically equivalent possibilities exist, and the curve in Figure 5 can be calculated from either equation (48) or equation (49) with appropriate values of the rate constants, where ki is the... 

Release of salicylic acid from benzaldehyde disalicyl acetal gives a bell-shaped pH-rate constant profile (Figure 6) analogous to lysozyme-catalysed reactions (Anderson and Fife, 1973). The maximum... 

Such experiments were repeated for eac compound at a variety of pH s and temperatures so that pH-rate constant profiles and activation energies could be obtained. Extraneous experimental complications such as sorption of the compound to container walls, incomplete extraction from aqueous solutions and possible catalysis by metal ions in solution were carefully monitored and accounted for in the final determination of aqueous phase hydrolysis rate constants. Of these possibilities, only sorption to container walls was observed to have a measurable effect on the experimental data. 

Figure 2. pH-rate constant profile for chlorpyrifos in distilled water at 25 °C. 

The o-carboxyl group in the acetal (177) enhances the rate of acetal ring opening by a factor of 220 compared with the analogous / -isomcr.142 Compounds with other o- and -derivatives (e.g. C02Me) have straightforward pH-log (rate constant) profiles with slopes of ca —1.0. 

FIGURE 5.26 pH-rate constant profile for the specific acid-base catalyzed hydrolysis of a water-soluble diaziridinyl benzoquinone derivative. [Graph reconstructed from data by Jain et al., AAPS National Meeting, Paper No. 2268, Indianapolis, IN, Oct. 29, 2000.]... 

Figure 5.29 illustrates the pH-rate constant profile for the hydrolysis of L-phenylalanine methyl ester (weak base, pKa = 7.11) at 25°C. When attempts are made to simulate the experimental data with Equation (5.167) over a wide range of pH values, the model seldom fits well, because the values of kobs differ by several orders of magnitude and nonlinear regression analysis does not converge. Therefore, it is recommended that the kinetic values be within less than a few orders of magnitude. A localized and stepwise simulation process is recommended. At very low or high pH, Equation (5.167) simplifies to... 

FIGURE 5.31 pH-rate constant profiles for the hydrolysis of aspirin (dotted line) and aspirin methyl ester (solid line). [Graph reconstructed from data by G. M. Loudon, J. Chem. Ed., 68, 973 (1991).]... 

The pH-rate constant profiles of aspirin and aspirin methyl ester are shown in Figure 5.31. The profiles for aspirin methyl ester and aspirin are partitioned into three and four zones, respectively. Distinctively, the aspirin methyl ester profile is expressed by Equation (5.158b). The aspirin profile has similar hydrolysis rates in the zones of very low and very high pH to the aspirin methyl ester profile. However, in the range of pH 3 to 7, aspirin shows one upward bend at a pH close to 3.5, which is about the pKa (=3.4) of aspirin. At pH 4 to 5, the hydrolysis rate of aspirin is... 

FIGURE 5.32 pH-rate constant profile of the hydrolysis of aspartame ( pKal =3.19 and pK = 8.14) at 25°C in water. [Graph reconstructed from data by Skwierczynski and Connors, Pharm. Res., 10, 1174 (1993).]... 

Figure 5.32 shows the pH-pseudo-ftrst-order rate constant profile of the degradation of aspartame (an ampholyte, pKal = 3.19 and pKa2 = 8.14). In the hydrolysis of aspartame, the protonated/undissociated form predominates at low pH (<3), while the deprotonated/dissociated form exists at high pH (>8). As demonstrated for monoprotic weak acids and weak bases, certain terms in the numerator of Equation (5.173) become negligible. For example, the hydrolysis of the protonated/undissociated form by OH-, of the protonated/dissociated form by H+ and OH-, and the deprotonated/dissociated form by H+ are not likely to occur. Then, Equation (5.173) for the ampholytic drug is written as ... 

Thevaluesof k2+ = 2.05xl0 5sec-1M-1 and k0 = 1.50 sec 1M 1 are estimated. Substituting these values into Equation (5.174) followed by nonlinear regression analysis gives other k values. Intuitively from the profile of pH 2 to 4, one can assume kj 0 = 0. As demonstrated for monoprotic and diprotic weak acids and weak bases, the pH-rate constant profile is dependent on the kinetic pathway of the hydrolysis. It can be seen from Figure 5.32 that at pH 3 to 4 and pH 4 to 9, k2>0 and k0 0 are the predominant processes of the hydrolysis of aspartame, respectively. 

FIGURE 5.41 pH-rate constant profile for the hydrolysis of aspirin in 0.5% aqueous ethanol solution at four temperatures. [Graph simulated from data by E. R. Garret, J. Am. Chem. Soc., 79, 3401 (1957).]... 

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