Hydrolysis kinetics substituent effects

A comparison of the kinetics of hydrolysis and isotopic exchange of amides A and B was carried out. Some of the data are given below. An interesting observation is that there is more C=0 exchange for A than for B. From this observation, and other data given, develop a stepwise mechanism for the hydrolysis of each amide and a qualitative comparison of the substituent effects on the various steps. 

The acid-catalysed hydrolysis of the acylal, 1-phenoxyethyl propionate (13), has been studied using the PM3 method in the gas phase. The kinetics and mechanism of the hydrolysis of tetrahydro-2-furyl and tetrahydropyran-2-yl alkanoates (14) in water and water-20% ethanol have been reported. In acidic and neutral media, kinetics, activation parameters, isotope-exchange studies, substituent effects, solvent effects and the lack of buffer catalysis pointed clearly to an Aai-1 mechanism with formation of the tetrahydro-2-furyl or tetrahydropyran-2-yl carbocation as the rate-limiting step (Scheme 1). There is no evidence of a base-promoted Bac2 mechanism up to pH 12. ... 

Structures have been determined for [Fe(gmi)3](BF4)2 (gmi = MeN=CHCF[=NMe), the iron(II) tris-diazabutadiene-cage complex of (79) generated from cyclohexanedione rather than from biacetyl, and [Fe(apmi)3][Fe(CN)5(N0)] 4F[20, where apmi is the Schiff base from 2-acetylpyridine and methylamine. Rate constants for mer fac isomerization of [Fe(apmi)3] " were estimated indirectly from base hydrolysis kinetics, studied for this and other Schiff base complexes in methanol-water mixtures. The attenuation by the —CH2— spacer of substituent effects on rate constants for base hydrolysis of complexes [Fe(sb)3] has been assessed for pairs of Schiff base complexes derived from substituted benzylamines and their aniline analogues. It is generally believed that iron(II) Schiff base complexes are formed by a template mechanism on the Fe " ", but isolation of a precursor in which two molecules of Schiff base and one molecule of 2-acetylpyridine are coordinated to Fe + suggests that Schiff base formation in the presence of this ion probably occurs by attack of the amine at coordinated, and thereby activated, ketone rather than by a true template reaction. ... 

Kinetic data at 35-55 °C of the neutral hydrolysis (pH 6.9-7.5) of a series of substituted benzoyl phosphates (66 X = 4-Me, H, 4-C1, 4-CN, 4-N02, 3,5-dinitro) revealed that sizeable substituent effects on both Aand A were apparent. This, it was claimed, showed the contribution of solvation of the leaving benzoate and a substituent-induced shift of the structure of the transition state.16... 

An important feature of reactions in solvent mixtures is the effect of substituents in the reactant on the kinetic parameters. As Foon and Hambly (1962) note with reference to the hydrolysis of a series of sulphonyl halides, it is possible to obtain almost any order for the rate constants by selection of the appropriate solvent mixture. The substituent effects also depend on the temperature and, in the case of bimolecular reactions, on the nature of the attacking group, e.g. OH- instead of H20 (Tommila, 1967). 

Numerous solvolytic studies on diarylmethyl derivatives have been carried out under a variety of conditions. The analysis of substituent effects in the solvolysis of the monosubstituted chlorides [22] was reported earlier (Yukawa and Tsuno, 1959 Yukawa etal., 1966). The purpose of this analysis is to clarify the effect of a fixed substituent Y in one ring on the substituent effect of the variable substituents X on the second ring. Three extensive sets of kinetic data for the solvolysis of X, Y-disubstituted benzhydryl systems under fixed conditions have been reported one for the ethanolysis (Nishida, 1967), one for the chloride hydrolysis in 85% aqueous acetone at 0°C (Fox and Kohnstam, 1964) and one for the bromide hydrolysis (Mindl et al., 1972 Mindl and... 

While these analyses were not altogether successful, the behaviour of the pA R+ substituent effect appears to resemble closely the behaviour of the kinetic (log/c) substituent effects in benzhydryl solvolyses. It is therefore remarkable that there is an excellent linear relationship (20) between log k for the hydrolysis and p/Cr+ for the diarylmethyl series over the range from X = Y = HtoX = Y= p-MeO (Fig. 16). 

Since the ir value is constitutive, the stereospecific nature of hydro-phobic bonding for drug-receptor interactions can be delineated by regression analyses with the tt values of substituents separately for each position of the congeners. Thus, the substituent effect on the emulsin hydrolysis of substituted phenylglucosides has been nicely delineated by analyzing kinetic constants separately for meta and para isomers. The meta substituents play no hydrophobic role in the enzyme-substrate complex formation 24). 

Reactives of Side-Chains of Monocyclic Thiophens. - The rate constants for the esterification of some 3-, 4-, and 5-substituted thiophen-2-carboxylic acids and of some 2- and 4-substituted thiophen-3-carboxylic acids with diazodiphenylmethane in methanol solution have been measured, and linear correlations gave information about the transmission of substituent effects. The rates of alkaline hydrolysis of ethyl thiophen-2-carboxylate in ethanol-water and DMSO-water media have been measured and compared with those of other heterocyclic esters. The kinetics of iodination of 2-acetylthiophen in methanol-water, using different carboxylate buffers, have been studied.Basicity constants have been measured for j3-(2-thienyl)-acrylamides and compared with those of the corresponding benzene and furan derivatives. The acidity constants of ( )-a-phenyl-j3-(2-thienyl)-acrylic acids and analogous furan-, selenophen-, and pyridine-substituted compounds have been measured, and have been rationalized by an equation involving separate contributions of polar, conjugative, and steric effects of the heterocycles. ... 

As in the case of hydrolysis, there has been a good deal of study of substituent effects, solvent effects, isotopic exchange, kinetics, and the catalysis of these processes. In contrast to hydrolysis, the alcoholysis reaction is reversible in both acidic and basic solutions. The key intermediate is the tetrahedral adduct. Its fate is determined mainly by the relative basicity of the two alkoxy groups. A tetrahedral intermediate generated by addition of methoxide ion to a p-nitrophenyl ester, for example, breaks down exclusively by elimination of the much less basic /j-nitrophenoxide ion. 

The deuterium kinetic isotope effect (fejjjo/ 030) for the hydrolysis of aspirin is 2.2. What does this tell you about the kind of catalysis exerted by the ort/io-carboxyl substituent Hint It is easier to break an O—H bond than an O—D bond.)... 

The hydrolysis kinetics of aliphatic esters (R, and R2 = alkyl groups) are also sensitive to electronic effects. The hydrolysis data for a series of aliphatic esters are summarized in Table 2.4. The addition of chloride substituents to the Rj group drastically increases the neutral and base hydrolysis rate constants. These data also demonstrate that as the steric bulk of R2 increases, there is a significant decrease in kb (compare ethyl acetate to t-butyl acetate). 

Analysis of the structure-reactivity cross-correlations shows the existence of isoparametric relationships in the reactions of Y-substituted benzyl bromides with X-substituted anilines in dioxane and in its mixtures with DMSO at 40 The kinetics of hydrolysis of 1-arylethyl ethers of salicyclic acid, catalysed intramolecularly by 0-CO2H, have been studied. Analysis of substituent effects in both arylethyl and leaving groups provides the most detailed available mechanistic insight into a reaction involving efficient intramolecular proton-transfer catalysis. The mechanism is very different from classical general acid-base catalysis. ... 

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