Selectivity in some electrophilic aromatic substitution reactions

Reactivity and selectivity are believed to be correlated with the position of the transition state on the reaction coordinate. With highly reactive electrophiles the shape of the reaction coordinate would be expected to be as in Fig. 9.3A. The transition state then resembles the reactants more closely that the a--complex. The positive charge on the ring is small, and the interaction with the substituent group resulting in preferential stabilization of a specific cr-complex is weak. With a less reactive electrophile, the transition state comes later, as in Fig. 9.3B. The new bond 

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 r-complex is 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. 

At this point, attention can be given to specific electrophilic aromatic substitution reactions. The kinds of data that have been especially pertinent to elucidating mechanistic detail include linear free-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 concerning reaction kinetics, isotope effects, and structure-reactivity relationships has permitted a quite thorough understanding of the steps in aromatic nitration. As indicated by the general mechanism for electrophilic substitution, there are three distinct steps  

Conditions under which each of the first two steps is rate-determining have been recognized. The third step is very rapid in nearly all cases, and therefore not amenable to direct kinetic investigation. 

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Table 10.4. Selectivity in Some Electrophilic Aromatic Substitution Reactions ...

Selectivity in some electrophilic aromatic substitution reactions... 

Such an explanation of the selectivity paradox is compatible with the concept of electron transfer mechanisms in an electrophilic aromatic substitution (for a general review of this concept see Refs. [144,145]). The electron transfer occurs at the stages of formation of the intermediate complex XLIV and the d-complex XLV. In 1959 Brown put forward a hypothesis that there should exist a charge transfer stage responsible for the formation of the 7r-complex XLIV in a nitration reaction. A similar view is held by some other authors [146-148], even if the adduct XLIV is not necessarily regarded as a 7r-complex. In the nitration and nitrosation reactions, the electron transfer from an activated aromatic nucleus onto the lower-lying vacant MO s of the ion acceptor is thermodynamically quite advantageous (20-111 kcal/mol), therefore the detailed representation of the reaction scheme of Eq. (5.13) ... 

The a-selectivity is illustrated by the fact that 2-alkyl-, > 2-methoxy-, > and 2-alkyIthio-thiophenes and alkyl thenyl sul-fides ° are metalated exclusively in the 5-position. In electrophilic aromatic substitution, as previously mentioned, an appreciable amount of 3-substitution is obtained with some of these groups. After acetalization ketones can also be metalated. Thus from the diethyl ketal of 2-acetylthiophene, 2-acetyl-5-thiophenealdehyde was obtained after metalation with n-butyllithium followed by the reaction of the metalorganic compound with A,A -dimethylformamide. ... 

For example, direct fluorinations with elemental fluorine are kept imder control in this way, at very low conversion and by entrapping the molecules in a molecular-sieve reactor. As with some other aromatic substitutions they can proceed by either radical or electrophilic paths, if not even more mechanisms. The products are dif ferent then this may involve position isomerism, arising from different substitution patterns, when the aromatic core already has a primary substituent further, there may be changed selectivity for imdefined addition and polymeric side products (Figure 1.31). It is justified to term this and other similar reactions new , as the reaction follows new elemental paths and creates new products or at least new... 

The empirical data for electrophilic aromatic substitution on benzocycloalkenes over a variety of reactions and conditions show a consistent trend of increased Cp selectivity due primarily to C deactivation, with some indication that Cp activation occurs in benzobicycloalkenes. Acidity work on the benzocycloalkenes and related pyridines demonstrates clearly the extent of deactivation. The rehybridization model of Finnegan and Streitweiser has been postulated to account for the deactivation. Thummel s correlation of C y -H P a provided the necessary link between rehybridization and deactivation. Theories involving bond fixation in the Wheland intmnediate deserve some further consideration but are not essential to an understanding of the present empirical data. 

A more interesting problem than the influence of substituents in the electrophilic reagent of azo coupling is the extremely high selectivity of the C-coupling reactions, relative to other electrophilic aromatic substitutions. Unsubstituted benzene does not react with any arenediazonium ion, 1,3,5-trimethoxybenzene reacts very slowly with strongly electrophilic diazonium ions only aromatic amines (e.g. N,N-dimethyl-aniline) or phenolate ions react very fast, in some cases close to diffusion control. 

The general mechanistic framework outlined in the preceding paragraphs must be elaborated by other details to fully describe the mechanisms of the individual electrophilic substitutions. The question of the identity of the active electrophile in each reaction is important. We have discussed the case of nitration, in which, under many circumstances, the electrophile is the nitronium ion. Similar questions arise in most of the other substitution processes. Other matters that are important include the ability of the electrophile to select among the alternative positions on a substituted aromatic ring. The relative reactivities of different substituted benzenes toward various electrophiles have also been important in developing a firm understanding of electrophilic aromatic substitution. The next section considers some of the structure-reactivity relationships that have proven to be informative. 

Hammett correlations also permit some insight into the reactivity and selectivity of electrophiles in aromatic substitution reactions. In general, the standard Hammett O substituent constant gives poor correlations with reactions involving electrophilic... 

Aromatic substrates are by far the most commonly used substrates in the rapidly expanding area of photoinduced electron transfer [1,2]. This is obviously due to the favourable location of the frontier molecular orbitals in such compounds. The same factor facilitates the formation of electron transfer donor-acceptor (EDA) complexes both in the ground state (these possibly are intermediates in some thermal reactions, e.g. selected electrophilic substitutions), and in the excited state (exciplexes). 

In aromatic electrophilic substitution, " the initial interaction between an electrophile and the aromatic n system is a multicenter interaction (of n-complex nature). The lack of substrate selectivity observed in some reactions of aromatic compounds with strong electrophiles (e.g., N()2 ) indicates that the initial multicenter complex is a separate well-defined intermediate,- " " Its nature was much discussed. Schofield et al. suggested it to be a solvent cage, whereas Perrin preferred a radical ion pair. There was general agreement of an initial intermediate involving the aromatic as an entity. The subsequent step affords a trivalent benzenium ion intermediate or a complex (Scheme 6.42). 

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