General acid catalysis, isotope effects

Salomaa P, Kankaanpena A, Lajunen M (1966) Protolytic cleavage of vinyl ethers. General acid catalysis, structural effects, and deuterium solvent isotope effects. Acta Chem Scand 20 1790-1801... 

Alkenes lacking phenyl substituents appear to react by a similar mechanism. Both the observation of general acid catalysis and the kinetic evidence of a solvent isotope effect are consistent with rate-limiting protonation with simple alkenes such as 2-metlQ lpropene and 2,3-dimethyl-2-butene. 

The general acid catalysis, the deuterium solvent isotope effects, and the lack of deuterium incorporation upon partial hydration in D2 0 are particularly convincing evidence for a rate-determining protonation and the discrete intermediacy of a vinyl cation such as 6. 

The solvent isotope effect produces an A-ratio (HOH/DOD) of three with isotope-independent A// of 17-18 kJ/mol. This result is more difficult to interpret, because it is unknown how many isotopic sites in the enzyme or water structure contribute to the isotope effect of 2-3. If a single site should be the origin of the effect, then the site could reasonably be a solvent-derived protonic site of the enzyme involved in general-acid catalysis of the hydride transfer, most simply by protonic interaction with the carbonyl oxygen of cyclohexenone or possibly by proton transfer to an olefinic carbon of cyclohexenone. 

Among the facts supporting this mechanism (which is an A-Se2 mechanism because the substrate is protonated in the rate-determining step) are (1) lsO labeling shows that in ROCH=CH2 it is the vinyl-oxygen bond and not the RO bond that cleaves 497 (2) the reaction is subject to general acid catalysis 498 (3) there is a solvent isotope effect when D2O is used.498 Enamines are also hydrolyzed by acids (see 6-2) the mechanism is similar. Ketene dithioacetals R2C=C(SR )2 also hydrolyze by a similar mechanism, except that the initial protonation step is partially reversible.499 Furans represent a special case of enol ethers that are cleaved by acid to give 1,4 diones. Thus... 

The carboethoxy stabilized secondary enamines, 25 and 26, were studied by Guthrie and Jordan68. In the absence of buffer, and at pH 5 to 6, acid catalysis is evident and a solvent kinetic isotope effect, (kH+/kD+) = 2.3, is found for 25. These results clearly support rate-controlling C-protonation of the enamine the catalytic constants are included in Table 9. Both 25 and 26 show general-acid catalysis of hydrolysis in the pH... 

Although buffers were used by Dixon and Greenhill to control the pH of their reaction solutions, the concentration of buffer components was very low (total [buffer] 10"2 M) and, perhaps for this reason, catalysis by buffers was not detected. Nor were experiments carried out in D20. Therefore two of the major criteria for rate-controlling proton transfer, general-acid catalysis and a primary kinetic solvent isotope effect were not demonstrated. Nevertheless the pH-rate profiles are indicative, for the most part, of a mechanism much like Scheme 1. 

It is possible that conjugated enamines such as enaminones hydrolyze by the mechanism shown in Scheme 2, a variation of Scheme 1 in which nucleophilic hydration occurs on an O-protonated enamine rather than on the C-protonated (iminium) ion. This mechanism has been proposed for the acidic hydrolysis of compounds 36 and 37. This mechanism cannot be considered established, however, as the experiments that would rule out C-protonation were not done. It is highly pertinent that hydrolyses of other conjugated enamines, 10,11, 25, 26,39 and 40, all obey the expectations of Scheme 1, equation 15, namely they exhibit general-acid catalysis and (for 25, 26, 39 and 40) primary kinetic solvent isotope effects. 

In the presence of picric acid, the reaction products were the same, but general acid catalysis could be observed. The solvent isotope effect was determined using a mixture of 82.5 % ethanol and 17.5 % water. If 38 % of the mobile (O-bonded) hydrogen of the solvent was replaced by deuterium the reaction rate was decreased by a factor of 1.45. Linear extrapolation to 100% deuteration led to an approximate result of kH/kD 2.2. Similar experiments referring to general catalysis and solvent isotope effects have been done for the ethanolysis of 9-diazo-fluorene, and similar results have been obtained [215]. 

If we speed up the slow step by adding to the molecule some feature that stabilizes the cation intermediate, general acid catalysis may be found. One example is the aromatic cation formed in the hydrolysis of cycloheptatrienone acetals. The normal kinetic isotope effect proclaims GAC. 

In the hydrolysis of diethylphenyl orthoformate no general base catalysis is observed. The steric effects of substituents on the imidazole catalyst are very small, and the activation parameters have been shown to have large negative entropies. These observations, in conjunction with a solvent isotope effect, point to participation of water molecules in the transition state, i.e., at least one water molecule intervenes between imidazolium ion and the ortho ester (see (66)). General acid catalysis is assumed <87JCS(P2)669>. 

Hydration was studied in aqueous HCl solution (approximately 3 x 10 M up to greater than 1 M) and, in carboxylic acid buffer solutions, all at 25 °C. General-acid catalysis was demonstrated (a = 0.6, a value very similar to that found by others and primary kinetic isotope effects were found (A h+/ d+) = 3.2 for 39 and 3.7 for 40, while (/chcojh/ hcojd) was 5.3 for 39 and 6.2 for 40. 

Figure 3.17 Molecular mechanisms giving rise to enhanced hydrolysis rates of glycosides with carboxylic acid groups. In the case of salicyl fi-glucoside, frontside nucleophilic attack is stereoelectronically prohibited and distinction between specific acid catalysis of the hydrolysis of the anion and intramolecular general acid catalysis was made on the basis of solvent isotope effects in related systems. ...

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