Proton rate-limiting

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. 

As with simple imines, the identity of the rate-limiting step changes with solution pH.. s the pH decreases, the rate of the addition decreases because protonation of the amino compound reduces the concentration of the nucleophilic unprotonated form. Thus, whereas the dehydration step is normalfy rate-determining in neutral and basic solution, addition becomes rate-determining in acidic solutions. 

This variation from the ester hydrolysis mechanism also reflects the poorer leaving ability of amide ions as compared to alkoxide ions. The evidence for the involvement of the dianion comes from kinetic studies and from solvent isotope effects, which suggest that a rate-limiting proton transfer is involved. The reaction is also higher than first-order in hydroxide ion under these circumstances, which is consistent with the dianion mechanism. 

D-Methylmalonyl-CoA, the product of this reaction, is converted to the L-isomer by methylmalonyl-CoA epunerase (Figure 24.19). (This enzyme has often and incorrectly been called methylmalonyl-CoA racemase. It is not a racemase because the CoA moiety contains five other asymmetric centers.) The epimerase reaction also appears to involve a carbanion at the a-position (Figure 24.20). The reaction is readily reversible and involves a reversible dissociation of the acidic a-proton. The L-isomer is the substrate for methylmalonyl-CoA mutase. Methylmalonyl-CoA epimerase is an impressive catalyst. The for the proton that must dissociate to initiate this reaction is approximately 21 If binding of a proton to the a-anion is diffusion-limited, with = 10 M sec then the initial proton dissociation must be rate-limiting, and the rate constant must be... 

Spontaneous dissociation of the protonated alcohol occurs in a slow, rate-limiting step to yield a carbocation intermediate plus water. 

Evidently, a pH of 4.5 represents a compromise between the need for some acid to catalyze the rate-limiting dehydration step but not too much acid so as to avoid complete protonation of the amine. Each individual nucleophilic addition reaction has its own requirements, and reaction conditions must be optimized to obtain maximum reaction rates. 

The kinetics and mechanism of formation of 2,3-naphthotriazole (6.49) were studied by Oh and Williams (1989). In aqueous solutions of 0.2-1.0 m HC104 the dependence of the reaction on acidity indicated simultaneous involvement of the protonated and unprotonated substrates (6.47 and 6.48 respectively). The unproton-ated form of 2,3-diaminonaphthalen (6.48) reacts with the nitrosyl ion (NO+) on encounter (rate constant k ). The 2-NH3 substituent reduces the reactivity of 6.47 by a factor of about 800 (ki/k2). The rate-limiting formation of the diazonium ion (Scheme 6-33) is followed by a rapid cyclization (Scheme 6-34). 

There are two cases in which the general base catalysis observed for an azo coupling reaction is due not to a rate-limiting proton transfer from the o-complex (Scheme 12-66) but to deprotonation of the coupling component when the species involved in the substitution is formed. These reactions are shown in Schemes 12-71 H I... 

Also considered as possibilities have been transition states involving IV, below, the conjugate base of II, and either RjNHJ or BH+ 29,30. This mechanism, with II and IV maintained at equilibrium by rapid, reversible proton transfers and BH + or R2NH2 assisting separation of the leaving group from intermediate IV in the rate-limiting step, may be formulated as... 

The experiments of Bott (17) and Noyce (19-21) show that a vinyl cation best represents the intermediate in the hydration of phenylacetylenes. In particular, the large solvent Isotope effects observed indicate a rate-limiting protonation and formation of a vinyl cation, for these values are not in agreement with solvent isotope effects observed for compounds which react by other possible mechanisms, such as one involving equilibrium formation of the vinyl cation followed by the slow attack by water. 

In contrast, the acid-catalyzed hydration of arylbenzoylacetylenes differs markedly from the hydration of a-unsaturated ketones. Hydration of unsaturated ketones has been shown to proceed via a 1,4-addition mechanism where protonation occurs on oxygen to give an oxonium salt, followed by attack of water at the 0-carbon to give a hydroxy enol. The rate-limiting step has been shown to be the protonation of the hydroxy enol (27) ... 

Evans found that molecular hydrogen was efficiently generated by the reaction of a simple diiron complex [CpFe(CO)2]2 (Fp2) with acetic acid (pA a = 22.3) in acetonitrile [202]. Electrochemical simulations revealed that Ep2, [CpEe(CO)2] (Fp ), and [CpFe(CO)2H] (FpH) were key intermediates in this catalytic mechanism (Scheme 61). Reduction of Fp2 produces both an Fp anion and an Fp radical, which is further reduced to give an Fp anion. The oxidation of the Fp anion by proton affords FpH. This protonation was found to be the rate-limiting step. The dimerization of the FpH generates Fp2 and H2. Alternatively, the FpH is reduced to afford the FpH anion, which is subsequently protonated... 

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