Kinetic isotope effects aromatic substitution

Table 10.6. Kinetic Isotope Effects in Some Electrophilic Aromatic Substitution Reactions...

A substantial body of data, including reaction kinetics, isotope effects, and structure-reactivity relationships, has permitted a thorough understanding of the steps in aromatic nitration. As anticipated from the general mechanism for electrophilic substitution, there are three distinct steps ... 

Bromination has been shown not to exhibit a primary kinetic isotope effect in the case of benzene, bromobenzene, toluene, or methoxybenzene. There are several examples of substrates which do show significant isotope effects, including substituted anisoles, JV,iV-dimethylanilines, and 1,3,5-trialkylbenzenes. The observation of isotope effects in highly substituted systems seems to be the result of steric factors that can operate in two ways. There may be resistance to the bromine taking up a position coplanar with adjacent substituents in the aromatization step. This would favor return of the ff-complex to reactants. In addition, the steric bulk of several substituents may hinder solvent or other base from assisting in the proton removal. Either factor would allow deprotonation to become rate-controlling. 

It is clear from the results that there is no kinetic isotope effect when deuterium is substituted for hydrogen in various positions in hydrazobenzene and 1,1 -hydrazonaphthalene. This means that the final removal of hydrogen ions from the aromatic rings (which is assisted either by the solvent or anionic base) in a positively charged intermediate or in a concerted process, is not rate-determining (cf. most electrophilic aromatic substitution reactions47). The product distribution... 

The electrophile E+ attacks the unhindered side of the still unsubstituted second aromatic ring. A proton (deuteron) is transferred from this ring to the second, originally substituted ring, from which it leaves the molecule. Thus, the electrophile enters, and the proton (deuteron) leaves the [2.2]paracyclophane system by the least hindered paths. Some migration of deuterium could be detected in the bromination of 4-methyl[2.2]paracyclophane (79). The proposed mechanism is supported by the kinetic isotope effects ( h/ d) found for bromination of p-protio and p-deuterio-4-methyl[2.2]paracyclophanes in various solvents these isotope effects demonstrate that proton loss from the a complex is the slowest step. 

An S Ar (nucleophilic substitution at aromatic carbon atom) mechanism has been proposed for these reactions. Both nonenzymatic and enzymatic reactions that proceed via this mechanism typically exhibit inverse solvent kinetic isotope effects. This observation is in agreement with the example above since the thiolate form of glutathione plays the role of the nucleophile role in dehalogenation reactions. Thus values of solvent kinetic isotope effects obtained for the C13S mutant, which catalyzes only the initial steps of these reactions, do not agree with this mechanism. Rather, the observed normal solvent isotope effect supports a mechanism in which step(s) that have either no solvent kinetic isotope effect at all, or an inverse effect, and which occur after the elimination step, are kinetically significant and diminish the observed solvent kinetic isotope effect. 

The most widely accepted mechanism for electrophilic aromatic substitution involves a change from sp2 to sps hybridization of the carbon under attack, with formation of a species (the Wheland or a complex) which is a real intermediate, i.e., a minimum in the energy-reaction coordinate diagram. In most of cases the rate-determining step is the formation of the a intermediate in other cases, depending on the structure of the substrate, the nature of the electrophile, and the reaction conditions, the decomposition of such an intermediate is kinetically significant. In such cases a positive primary kinetic isotope effect and a base catalysis are expected (as Melander43 first pointed out). 

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... 

Perdenteration of the methylene hnker affords a relatively kinetically stable complex, which allows for the monitoring of exogenons snbstrate oxidations. When (7) is exposed to cold (-95 °C) acetone solntions of the lithium salts of para-substituted phenolates, clean conversion to the corresponding o-catechols is observed. Deuterium kinetic isotope effects (KIEs) for these hydroxylation reactions of 1.0 are observed, which is consistent with an electrophilic attack of the peroxo ligand on the arene ring. An electrophilic aromatic substitution is also consistent with the observation that lithium jo-methoxy-phenolate reacts substantially faster with (7) than lithium / -chloro-phenolate. Furthermore, a plot of observed reaction rates vs. / -chloro-phenolate concentration demonstrated that substrate coordination to the metal center is occurring prior to hydroxylation, and thus may be an important feature in these phenolate o-hydroxylation reactions. 

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