Intermolecular General Acid Catalysis

2 Simultaneous Occurrence of Both Intermolecular General Acid and General Base Catalysis 

The magnitude of rate constants for GA- and GB-catalyzed reactions depends on (1) the sensitivity of the reaction rate to GA and GB catalysis and (2) the acidity of GA and basicity of GB, respectively. If the rate of a nucleophilic reaction is significantly and equally sensitive to both GA and GB catalysis, where GB also acts as a nucleophile, then the incorporation of GB-catalyzed term, kgb[NuH] in Equation 2.57 with [Buf]x = 0, gives Equation 2.61 

In view of Equation 2.61, apparent buffer-catalyzed third-order rate constant (kb) may be expressed as 

It is evident from Equation 2.62 that the plot of kb/(fa fa ) vs. ag should yield a straight line with definite intercept (= kgb) and definite slope (= kga/Ka ). 

Pseudo-first-order rate constants (k bs) for the nucleophilic reaction of CH3NHOH with A-ethoxycarbonylphthalimide (53), obtained at ditferent total concentration of acetate buffer ([BufJx) of a constant pH in the presence of 0.004-M CH3NHOH, follow the relationship k bs = kb[Buf]x which indicates that buffer-independent cleavage of 53 is insignificant compared to kb[Buf x under the imposed reaction conditions. The general rate law for the cleavage of 53 under such experimental conditions is expressed by Equation 2.63 

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Intermolecular general acid-catalysis occurs in a very limited number of known hydrolysis reactions. The hydrolysis of simple amides is susceptible to general acid catalysis by acetic acid at elevated temperatures. General acid catalysis in phosphate buffers is observable in one instance, the lactonization of 2-(hydroxymethyl)-benzoic acid (Weeks, 1965). Small intermolecular general acid terms have been observed 11 ... 

Intermolecular General Acid Catalysis of Glycoside Hydrolysis... 

Figure 3.28 Nucleophilic participation by carboxylate in the departure of various leaving groups from mixed acetals of phthalic hemialdehyde Rate enhancements of these spontaneous processes of 100 for 3,5-dichloro-phenolate departure, 22 for thiophenolate departure " and 20 for catechol monoanion departure were estimated from the rates of the p-phthalic derivatives intermolecular general acid catalysis of the catechol was also accelerated.

Brown and Kirby [46] found relatively efficient intramolecular general acid catalysis for the hydrolysis of the three acetals 3.10, 3.11 and 3.12 (Scheme 2.21). Acetals of benzaldehyde were used to ensure measurable rates of reaction for the much less reactive aliphatic systems. They offered the further advantage that EMs could be estimated, since intermolecular general acid catalysis can be observed for dialkyl acetals of benzaldehyde. 

Intermolecular general acid catalysis of the hydrolysis of acetals and ketals Fig. 8 shows, in general terms, the reaction profile for the specific acid-catalysed hydrolysis of an acetal or a ketal. 

LII and 1.28 for LIII, were similar to those observed in the intermolecular general acid catalysis of benzylidene catechol (XLIII) (1.4-1.5) [138]. 

Since compounds LIII, LIV, and LV are the salicyl analogues of compounds XLIII, XLI and XLII, in which intermolecular general acid catalysis is observed, it is possible to estimate the effective molarity of the carboxylic acid group acting as a general acid in these salicyl acetals. Figures of around 10 M for LIII [138], and 10 10 and 10 M are estimated for LIV, LV (R = Et) and LV (R = Me), respectively [142]. The effective molarity is not sensibly altered by substituents in the salicyl moiety of LV. 

S.9.3 Kinetic Ambiguity of the Assignment of Intermolecular General Acid Catalysis... 

Derive the general expression for the observed rate constant for hydrolysis of A as a function of pH. Assume, as is the case experimentally, that intramolecular general acid catalysis completely outweighs intermolecular catalysis by hydronium ion in the pH range of interest. Does the form of your expression agree with the pH rate profile given for this reaction in Fig. 8.6 (p. 489) ... 

Section III (Table H), intramolecular general acid catalysis, is the smallest because this mechanism is less common and because where it is observed (mostly in acetal chemistry) the corresponding intermolecular reactions often cannot be detected. 

The usual method for establishing partially rate-limiting proton transfer, determination of the rate constants in D2O, would give ambiguous results (Bruice and Piszkiewicz, 1967). However, intramolecular general acid catalysis [equation (48)] is the preferred mechanism in view of the intermolecular buffer acid catalysis observed with the unsubstituted compounds. General acid catalysis [75] should therefore be favoured in the intramolecular reaction. 

The ratio of rate constants for intramolecular general acid catalysis of the hydrolysis of [73] and intermolecular formic acid-catalysed hydrolysis of 2-phenoxytetrahydropyran is 580 M, a minimum value since the intramolecular reaction was studied at 15° while the bimolecuUir rates were measured at 50°. The ratio would be much larger if comparisons could be made at the same temperature... 

The intermolecular general-base catalysis of the hydrolysis may also be measured. Comparing the rate constants for this with those of the intramolecular reaction shows that a 13-M solution of an external base is required to give the same first-order rate as the intramolecular reaction has.12 The effective concentration of the carboxylate ion in aspirin is therefore 13 M. This is a typical value for intramolecular general-acid-base catalysis. 

The mechanism of the intramolecular general acid catalysis of the oxygen esters has not been established since the possible formation of anhydride intermediates has not been thoroughly investigated. The hydrolysis of phthalamic acid has been shown to proceed through an anhydride intermediate, detected by double labeling experiments (Bender et al., 1958a), as does the aminolysis of succinic acid. In these cases, the reaction may involve either a four-center path, symbolised by 40, or involve prior protonation followed by intermolecular attack by the carboxylate anion (41). 

Estimates of effective molarities in general acid catalysis of acetals require the analogous intermolecular reaction to be observable and therefore, as we have seen in the previous section, for the oxocarbenium ion to be particularly stable. The termolecular processes corresponding to the hydrolysis of salicyl... 

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