Substitution, electrophilic isotope effects

The occurrence of a hydrogen isotope effect in an electrophilic substitution will certainly render nugatory any attempt to relate the reactivity of the electrophile with the effects of substituents. Such a situation occurs in mercuration in which the large isotope effect = 6) has been attributed to the weakness of the carbon-mercury bond relative to the carbon-hydrogen bond. The following scheme has been formulated for the reaction, and the occurrence of the isotope effect indicates that the magnitudes of A j and are comparable ... 

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. 

This effect is observable within a series of very similar electrophiles. Zollinger27 found that in reactions of diazonium ions substituted with 4-C1, 3-C1, and 3-N02 substituents (i.e. the reactivity and electron-withdrawing power of the ion increased along the series) the respective kinetic isotope effects were 6.55, 5.48 and 4.78. 

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... 

Apart from a few studies (ref. 7), the use of deuterium kinetic isotope effects (kie s) appears to have had limited use in mechanistic studies of electrophilic bromination of olefins. Secondary alpha D-kie s have been reported for two cases, trans-stilbene fi and p-substituted a-d-styrenes 2, these giving relatively small inverse kie s of... 

Isotope Effects. If the hydrogen ion departs before the arrival of the electrophile (SeI mechanism) or if the arrival and departure are simultaneous, there should be a substantial isotope effect (i.e., deuterated substrates should undergo substitution more slowly than nondeuterated compounds) because, in each case, the C—H bond is broken in the rate-determining step. However, in the arenium ion mechanism, the C—H bond is not broken in the rate-... 

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. 

A reaction described as Sn2, abbreviation for substitution, nucleophilic (bimolecular), is a one-step process, and no intermediate is formed. This reaction involves the so-called backside attack of a nucleophile Y on an electrophilic center RX, such that the reaction center the carbon or other atom attacked by the nucleophile) undergoes inversion of stereochemical configuration. In the transition-state nucleophile and exiphile (leaving group) reside at the reaction center. Aside from stereochemical issues, other evidence can be used to identify Sn2 reactions. First, because both nucleophile and substrate are involved in the rate-determining step, the reaction is second order overall rate = k[RX][Y]. Moreover, one can use kinetic isotope effects to distinguish SnI and Sn2 cases (See Kinetic Isotope Effects). 

The decomposition of the reduced complex is facilitated, most probably, by an electrophilic substitution of I+ by H+. This is a relatively fast step, as no add catalysis or H-D isotope effect could be demonstrated. The presence of Cu(I) in a favorable position close to the iodine atom facilitates the reduction of the ligand. 

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 ... 

Problem 11.6 Sulfonation resembles nitration and halogenation in being an electrophilic substitution, but differs in being reversible and in having a moderate primary kinetic isotope effect. Illustrate with diagrams of enthalpy H) versus reaction coordinate. ... 

---