Proton Transfer as the Rate-Determining Step

Identification of Proton Transfer as the Rate-Determining Step 1. General acid catalysis 

This is usually generalized as shown in equation (2) to take account of 

Sometimes the observation of general acid catalysis may be sufficient to identify the mechanism with considerable confidence. For example, in aromatic proton exchange catalyzed by ammonium salts, the only structurally attractive A-2 mechanism, shown in equations (4) and (5), violates the principles of microscopic reversibility. Thus the elimination of the A-l mechanism leaves only the A-SE2 mechanism. In a more 

Ethyl vinyl ether hydrolysis 0-66 Kreevoy and Eliason, unpublished 

Isobutenylmercuric bromide cleavage 0-69 Kreevoy and Landholm, unpublished 

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The isotope effects clearly point to a proton transfer as the rate-determining step, and it is possible to formulate the following simple picture of the reaction. Protonation of DDM yields a diazonium ion which loses nitrogen to form a benzhydryl cation which then reacts according to the pattern illustrated above. However, such a scheme fails to incorporate an important observation. It was foxmd that, for reaction with im-dissociated acids, addition of a salt of the acid has no effect on the... 

A theoretical study using the density functional theory (DFT) method has been performed to rationalize the mechanism of the reactions between 1,3-dialkynes and hydroxylamine or hydrazine for the formation of 3,5-disubstituted isoxazoles or pyrazoles, respectively The computational results support a bimolecular proton transfer as the rate-determining step providing valuable clues for the use of Bronsted acid/base catalysts to promote the cyclization reaction (14OBC7503). 

Notice that specific acid catalysis describes a situation in which the reactant is in equilibrium with regard to proton transfer, and proton transfer is not rate-determining. On the other hand, each case that leads to general acid catalysis involves proton transfer in the rate-determining step. Because of these differences, the study of rates as a function of pH and buffer concentrations can permit conclusions about the nature of proton-transfer processes and their relationship to the rate-determining step in a reaction. 

It should be noted that there is a kinetic isotope effect on the normal reaction (9.11) when the a-deuterated compound is used as the substrate. A similar effect is found when the deuterated suicide inhibitor is used. Thus, both reactions involve a proton transfer in the rate-determining step of the reaction. It has also been shown that a sample of the allenic intermediate that is prepared chemically does in fact irreversibly inhibit the enzyme.18... 

In the presence of colloidal Pt, the decay of the reduced viologen was enhanced, presumably because of electron transfer to Pt and this decay became extremely rapid when the solution was acidified with 0.5 mol dm-3 H2S04. However, when EDTA was added to the system, hydrogen production was not observed, as EDTA is not an efficient electron donor (to [Ru(bipy)3]3+) at this pH. Nevertheless, hydrogen was evolved on irradiation (in the presence of EDTA) at neutral pH, although much more slowly than in a system containing MV2+, and in fact PV+ accumulated. This points to proton reduction as the rate determining step and the effect is ascribed to a shift... 

Scheme 5.4 A revised mechanism, which underlines the importance of the proton-transfer, as the rate-determining and stereo-determining steps.

The discussion of experimental methods is divided into two sections Sect. 2.1, where direct measurements of proton transfers such as (1) and (2) are described and Sect. 2.2, which is concerned with kinetic measurements of an overall reaction with a mechanism in which proton transfer is the rate-determining step. 

Knowing rate data in pure H2O and D2O, having available thermodynamic data on lyonium ion acidities, and by assuming the Bronsted catalysis law, it is an easy matter to calculate rates in mixed solvents based on (a) proton transfer as a rate-determining step, or (b) pre-equilibrium proton transfer. The present system adheres to rate-determining proton transfer, and thus A-2 mechanisms are eliminated. The agreement between theory and experimental values suggests that special features... 

Proton transfer is the rate-determining step, as is demonstrated by general acid catalysis and solvent isotope effect data. ... 

We have used inter- and intramolecular kinetic isotope effects to examine the mechanism of these Lewis acid catalyzed ene reactions. The Lewis acid catalyzed ene reaction has traditionally been though to proceed through either a concerted pericyclic mechanism or a stepwise reaction with a zwitterionic intermediate. We found that the intermolecular isotope effect in the Me2AlQ catalyzed ene reaction of formaldehyde is 1.3 with methylenecyclohexane and methylenecyclohex-ane-2,2,6,6- 4 and 1.4 with 2,3-dimethyl-2-butene and 2,3-dimethyl-2-butene- /i2. Since secondary iotope effects could be responsible for these results, these values are consistent with either a stepwise or concerted mechanism. Intramolecular isotope effects were determined to be 2.9 and 2.7 with 2 and 3, respectively. These substantial intramolecular isotope effects coupled with the small intermolecular isotope effects indicate that the reaction is stepwise with proton transfer following the rate determining step. In an intramolecular competition such as the ene reactions of formaldehyde with 2 and 3 an isotope effect will still be observed if the hydrogen transfer occurs... 

Complex 3 is stable only at low temperatures and evolves H2 above 230 K yielding [CpW(C0)2(fr-/c,C c,0-CO)- M( PCP)] as a thermodynamic reaction product [31], The proton transfer is the rate-determining step of the reaction, which is faster for the more basic Pd analog. The activation parameters determined (Table 8.3) indicate a highly ordered transition state and are similar to those found for the formation of i -H2 complexes (Fig. 8.5) [33] despite the difference in the transition state structure. 

The reactivity of carbon-carbon double bonds toward acid-catalyzed addition of water is greatly increased by electron-releasing substituents. The reaction of vinyl ethers with water in acidic solution is an example that has been extensively studied. With these substrates, the initial addition products are unstable hemiacetals which decompose to a ketone and an alcohol. Nevertheless, the hydration step is rate-determining, and the kinetic results pertain to this step. The mechanistic features that have been examined are similar to those for hydration of simple alkenes. Proton transfer is the rate-determining step, as is demonstrated by general acid catalysis and solvent isotope effect data. ... 

The proton-induced disproportionation and the oxidation of superoxide have been assessed with respect to the conditions necessary for the production of singlet or triplet state dioxygen.The disproportionation in strongly acid conditions is of second order with respect to [O2], but with less acidic systems such as phenols and water the rate is first order with respect to superoxide and to acidic reagent, proton transfer being the rate-determining step. " ... 

As demonstrated in this review, photoinduced electron transfer reactions are accelerated by appropriate third components acting as catalysts when the products of electron transfer form complexes with the catalysts. Such catalysis on electron transfer processes is particularly important to control the redox reactions in which the photoinduced electron transfer processes are involved as the rate-determining steps followed by facile follow-up steps involving cleavage and formation of chemical bonds. Once the thermodynamic properties of the complexation of adds and metal ions are obtained, we can predict the kinetic formulation on the catalytic activity. We have recently found that various metal ions, in particular rare-earth metal ions, act as very effident catalysts in electron transfer reactions of carbonyl compounds [216]. When one thinks about only two-electron reduction of a substrate (A), the reduction and protonation give 9 spedes at different oxidation and protonation states, as shown in Scheme 29. Each species can... 

However, it is difficult to reconcile the observed relative reactivities of hydrocarbons with a mechanism involving electron transfer as the rate-determining process. For example, n-butane is more reactive than isobutane despite its higher ionization potential (see Table VII). Similarly, cyclohexane undergoes facile oxidation by Co(III) acetate under conditions in which benzene, which has a significantly lower ionization potential (Table VII), is completely inert. Perhaps the answer to these apparent anomalies is to be found in the reversibility of the electron transfer step. Thus, k-j may be much larger than k2 for substrates, such as benzene, that cannot form a stable radical by proton loss from the radical cation [Eqs. (224) and (225)]. With alkanes and alkyl-substituted arenes, on the other hand, proton loss in Eq. (225) is expected to be fast. 

These researchers present a number of arguments and evidence, including large deuterium kinetic isotope effects, in support of a mechanism involving proton-tunneling in a charge transfer complex (equation 29), as the rate-determining step for the reaction of the hindered aryloxyl radical, ArO , with phenolic antioxidants and they propose that the mechanism applies equally well to attack by peroxyl radicals, R—O—O , on phenols. 

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