Isotope effects electrophilic aromatic substitution

There are several lines of evidence pointing to formation of a complexes as intermediates in EAS. One approach involves measurement of isotope effects on the rate of substimtion. If removal of the proton at the site of substitution is concerted with the introduction of the electrophile, a primary isotope effect is expected when electrophilic attack on the ring is rate determining. This is not the case for nitration. Nitration of aromatic substrates partially labeled by tritium shows no selectivity between protium-and tritium-substituted sites. Similarly, the rate of nitration of nitrobenzene is identical to that of penta-deuterio-nitrobenzene. ... 

The azo coupling reaction proceeds by the electrophilic aromatic substitution mechanism. In the case of 4-chlorobenzenediazonium compound with l-naphthol-4-sulfonic acid [84-87-7] the reaction is not base-catalyzed, but that with l-naphthol-3-sulfonic acid and 2-naphthol-8-sulfonic acid [92-40-0] is moderately and strongly base-catalyzed, respectively. The different rates of reaction agree with kinetic studies of hydrogen isotope effects in coupling components. The magnitude of the isotope effect increases with increased steric hindrance at the coupler reaction site. The addition of bases, even if pH is not changed, can affect the reaction rate. In polar aprotic media, reaction rate is different with alkyl-ammonium ions. Cationic, anionic, and nonionic surfactants can also influence the reaction rate (27). 

Isotope effects are also useful in providing insight into other aspects of the mechanisms of individual electrophilic aromatic substitution reactions. In particular, because primary isotope effects are expected only when the breakdown of the c-complex to product is rate-determining, the observation of a substantial points to a rate-... 

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

At this point, attention can be given to specific electrophilic substitution reactions. The kinds of data that have been especially useful for determining mechanistic details include linear ffee-energy relationships, kinetic studies, isotope effects, and selectivity patterns. In general, the basic questions that need to be asked about each mechanism are (1) What is the active electrophile (2) Which step in the general mechanism for electrophilic aromatic substitution is rate-determining (3) What are the orientation and selectivity patterns ... 

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 ... 

The reason for this difference in selectivity of different electrophilic reagents between the 2- and 3-positions must be sought in the finer details of the mechanism of electrophilic aromatic substitution Melander and co-workers are studying this problem by means of isotope effects. 

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... 

Aromatic compounds react with mercuric salts to give arylmercury compounds.69 Mercuric acetate or mercuric trifluoroacetate are the usual reagents.70 The reaction shows substituent effects that are characteristic of electrophilic aromatic substitution.71 Mercuration is one of the few electrophilic aromatic substitutions in which proton loss from the a complex is rate determining. Mercuration of benzene shows an isotope effect kB/kD = 6,72 which indicates that the [Pg.1026]

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. 

Problem 11.3 How does the absence of a primary isotope effect prove experimentally that the first step in aromatic electrophilic substitution is rate-determining ... 

Now that we have determined that the intermediate in electrophilic aromatic substitution is usually a a complex (see, however, p. 394), let us return to a consideration of Reaction 7.76. Two factors probably combine to cause the observed isotope effect and base catalysis. First, the strong electron-donating groups stabilize the intermediate 76 (Equation 7.77) and make departure of the proton more difficult than proton loss in many other electrophilic substitutions. [Remember, however, that k1 < k2 (see p. 386).] Second, steric interactions between the large diazonium group and the nearby substituents increase the rate... 

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). 

A C—H bond is broken faster than is a C—D bond. This rate difference (isotope effect, kH/kD) is observed only if the C—H (or C—D) bond is broken in the rate-determining step. If no difference is observed, as is the case for most aromatic electrophilic substitutions, C—H bond-breaking must occur in a fast step (in this case the second step). Therefore, the first step, involving no C—H bond-breaking, is rate-determining. This slow step requires the loss of aromaticity, the fast second step restores the aromaticity. 

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... 

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