Specific acid catalysis, isotope effects

The kinetic data based on the demonstration of specific acid catalysis in buffers, solvent isotope effects and acidity functions all support mechanisms where the proton-transfers are fast. It is possible to write equations which accommodate these facts together with the first-order dependence on hydrazo-compound and the concurrent first and second-order dependence on acidity. These are... 

This scheme requires a rate-determining (second) proton-transfer, against which there is considerable experimental evidence in the form of specific-acid catalysis, the solvent isotope effect and the hg dependence discussed earlier. Further, application of the steady-state principle to the 7i-complex mechanism results in a rate equation of the form... 

The kinetic solvent isotope effects, h.o/ d,o> range between 2 and 4 in the case of compounds 2 (Noyce et al., 1965, 1967 Noyce and Schiavelli 1968b Noyce and De Bruin, 1968) and between 1-7 and 2 0 in the case of compounds 3 (Stamhuis and Drenth, 1963a Drenth and Hogeveen, 1960). The observed values accord with the idea of a rate-limiting proton transfer to the triple bond a small inverse isotope effect would have been observed in the case of specific acid catalysis (Noyce et al., 1967). 

The inverse solvent deuterium isotope effect indicates specific acid catalysis (pp. 1102-4) and the modest negative entropy of activation suggests some bimolecular involvement. There are various mechanisms you might propose but the right one must surely involve cleavage of the three-membered ring in the protonated amine. The second or possibly the third step could be rate-determining. 

The racemizalion doesn t include that last step, rate-determining in the dehydration. Now w. an inverse solvent deuterium isotope effect indicating specific acid catalysis. The loss of wa -. form the same cation is now Ure slow step. The large Hammett p value also suggests the fonr.i the racem/zat/on mechanism... 

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. ...

Specific acid catalysis is also restricted to biologically noncompatible conditions because amides are protonated in oxygen rather than nitrogen with pKa values in the range of <0 [63,64]. The rarity of intermolecular acid/base effects on CTI was affirmed by the kinetic deuterium solvent isotope effects (KSIE) of about 1.0, indicating that the mechanism of spontaneous isomerization does not involve a proton-in-flight [29,42,65]. 

The first reaction has a normal kinetic isotope effect (RCO2H reacts faster than RCO2D) while the second has an inverse deuterium isotope effect (RCO2H reacts slower than RCO2D). This suggests that there is a ratedetermining proton transfer in the first reaction but specific acid catalysis in the second (i.e. fast equilibrium proton transfer followed by slow reaction of the protonated species). Protonation occurs at carbon in both reactions, and this can be a slow step. 

An inverse solvent isotope effect (kjDjO] > k[H20]) is indicative of specific acid catalysis. 

Alkenes lacking phenyl substituents appear to react by a similar mechanism. Both the observation of general acid catalysis and a solvent isotope effect are consistent with rate-limiting protonation with simple alkenes such as 2-methyl-propene and 2,3-dimethyl-2-butene. The observation of general acid catalysis rules out an alternative mechanism for alkene hydration, namely, water attack on an alkene-proton complex. The preequilibrium for formation of such a complex would be governed by the acidity of the solution, and so this mechanism would exhibit specific acid catalysis. 

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