Nitrosation isotope effects

The deuterium isotope effect is thought to arise from the effect on the equilibrium position of this A-nitrosation. This is also the case for the diazotization of aniline, but the isotope effect is larger, because two deprotonations are involved in the kinetics. 

The conclusions from the foregoing studies with phenol have been challenged by Challis and Lawson121, who find that rates of nitrosation (shown graphically) pass through a maximum at about 8 M perchloric acid, and also that the reaction shows a large primary kinetic isotope effect at 0.7 °C (Table 27). Hence loss of a... 

A large primary isotope effect kH/kD = 3.6 had also been found earlier by Ibne-Rasa122 in the nitrosation of 2,6-dibromophenol in the 4 position which was also shown to be base-catalysed. These values are not unexpected in view of the isotope effect found with diazonium coupling which involves a similarly unreactive electrophile, so that the rate-determining transition state will be displaced well towards products. Furthermore, the intermediate will have a quinonoid structure and will, therefore, be of low energy consequently, the energy barrier for the second step of the reaction will be high. 

It is claimed that the limiting value of k bs, 2.81 x 10" sec-1, represents the rate coefficient for the rearrangement reaction above (k,). The ring deuterium isotope effect kH kD was re-determined for this individual rate coefficient for rearrangement by finding the limiting value in the presence of added N-methylaniline and was found to be 2.4 at two different acidities, as compared with 1.7 for the ratio of the observed composite rate coefficients, as expected, since no isotope effect would be predicted for the de-nitrosation step. 

The formation of the Wheland intermediate from the ion-radical pair as the critical reactive intermediate is common in both nitration and nitrosation processes. However, the contrasting reactivity trend in various nitrosation reactions with NO + (as well as the observation of substantial kinetic deuterium isotope effects) is ascribed to a rate-limiting deprotonation of the reversibly formed Wheland intermediate. In the case of aromatic nitration with NO, deprotonation is fast and occurs with no kinetic (deuterium) isotope effect. However, the nitrosoarenes (unlike their nitro counterparts) are excellent electron donors as judged by their low oxidation potentials as compared to parent arene.246 As a result, nitrosoarenes are also much better Bronsted bases249 than the corresponding nitro derivatives, and this marked distinction readily accounts for the large differentiation in the deprotonation rates of their respective conjugate acids (i.e., Wheland intermediates). 

C-Nitrosation of aromatic substrates appears to follow the familiar two-stage A-Sg2 process for aromatic electrophilic substitution (Scheme 5). Such reactions are often characterized by quite large primary kinetic isotope effects... 

The reactivity of a large number of amides (of widely differing structure) in acid-catalysed nitrosation has been determined (Mirvish, 1975). There appears to be no correlation between the rate constants and the basicity of the amides. In this case (Scheme 7 X = H O) it is not known what the effective rate-limiting step is. Further studies in this area would be helpful, particularly using the solvent kinetic isotope effect. 

A study of the kinetics of nitrosation of iV,iV -dimethyl-A"-cyanoguanidine in acid media (Scheme 13) [where the substrate exists as its conjugate acid (130)] has established that the mechanism of the reversible reaction is similar to that found for nitrosation of amides and ureas, rather than amines (for which attack of the nitrosating agent on the free base is usually rate limiting).The reaction, which is subject to general-base catalysis but not influenced by halide ion, involves reversible rate-limiting proton transfer in the final step and exhibits solvent deuterium isotope effects of 1.6 and... 

Isotope effects are also useful in providing insight into other aspects of the mechanisms of individual electrophilic aromatic substitution processes. In particular, since primary isotope effects are expected only when the breakdown of the rate-determining, the observation of a substantial kn/ko points to rate-determining deprotonation. Some typical isotope effects are summarized in Table 9.7. While isotope effects are rarely observed for nitration and halogenation, Friedel-Crafts acylation, sulfonation, nitrosation, and diazo coupling provide examples in which the rate of proton abstraction can control the rate of substitution. 

The final step in the S Ar reaction mechanism involves deprotonation of the a-complex intermediate to regenerate the aromatic x-system, and this is expected to be a very fast step. Since the C—H bond is not being broken in a rate-determining step, there is usually little or no detectable kinetic isotope effect (KIE) for S Ar reactions [61]. Thus, studies of KlEs are also consistent with the involvement of the a-complex. Larger KIEs have been observed in conversions involving weak electrophiles, such as nitrosations and diazonium coupling reactions [61c]. 

Nitrosation of amines has continued to attract attention. 2-(Hydroxyethyl)pi-peridine has been found to react with nitrite by attack of the nitrosonium species on the oxygen atom of the protonated amine, followed by NO transfer from O to N and proton loss in a rate-limiting step. In D2O the isotope effect, k i/kx) = 2.22, is higher than that (1.67) for nitrosation of thiomorpholine for which the conformational requirement is more restrictive. 

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