Ar-SE reactions

Electrophilic Aromatic Substitutions via Sigma Complexes ( Ar-SE Reactions )... 

The electrophilic aromatic substitution via sigma (Wheland) complexes, or the Ar-SE reaction, is the classical method for functionalizing aromatic compounds. In this section, we will focus on the mechanistic foundations as well as the preparative possibilities of this process. 

For an Ar-SE reaction to be able to occur, first the actual electrophile must be produced from the reagent (mixture) used. Then this electrophile initiates the aromatic substitution. It takes place, independently of the chemical nature of the electrophile, according to a two-step mechanism (Figure 5.1). A third step, namely, the initial formation of a -complex from the electrophile and the substrate, is generally of minor importance for understanding the reaction event. 

In the first step of the actual Ar-SE reaction, a substituted cyclohexadienyl cation is formed from the electrophile and the aromatic compound. This cation and its derivatives are generally referred to as a sigma or Wheland complex. Sigma complexes are described by at least three carbenium ion resonance forms (Figure 5.1). There is an additional resonance form for each substituent, which can stabilize the positive charge of the Wheland complex by a pi electron-donating (+M) effect (see Section 5.1.3). This resonance form is an all-octet formula. 

Fig. 5.1. The common reaction mechanism for all Ar-SE reactions. Almost always we have X = H and rarely X = tert-Bu or X = S03H.

In the second step of the Ar-SE reaction, an aromatic compound is regenerated by cleaving off a cation from the C atom that reacted with the electrophile. Most often the eliminated cation is a proton (Figure 5.1, X = H or X = H ). 

In a few cases, cations other than the proton are eliminated from the sigma complex to reconstitute the aromatic system. The ferf-butyl cation (Figure 5.1, X = tert-Bu) and proto-nated S03 (Figure 5.1, X = SOsH) are suitable for such an elimination. When the latter groups are replaced in an Ar-SE reaction, we have the special case of an ipso substitution. Among other things, ipso substitutions play a role in the few Ar-SE reactions that are reversible (Section 5.1.2). 

Strictly speaking there is only indirect evidence for the occurrence of sigma complexes as Side Note 5.1. short-lived intermediates of Ar-SE reactions. Formed in the rate-determining step, sigma com- Stable Cyclohexadienyl plexes completely explain both the reactivity and regioselectivity of most Ar-SE reactions (cf. Cations Section 5.1.3). In addition, the viability of short-lived sigma complexes in Ar-SE chemistry is supported by the fact that stable sigma complexes could be isolated in certain instances. 

Fig. 5.5. De-tert-butylation via Ar—SE reaction. The sequence consisting of tert-butylation and de-tert-butyla-tion can in terms of a protecting group strategy be employed in the regioselective synthesis of a multiply substituted benzene derivative (cf. Figures 5.28 and 5.33).

Fig. 5.6. De-tert-butylation/re-tert-butylation as a possibility forisomerizing tert-butylated aromatic compounds via Ar-SE reactions.

In conclusion we can make the following statement most Ar-SE reactions are irreversible because they have a sufficiently strong driving force and, at the same time, because they can be carried out under sufficiently mild conditions. The most important reversible Ar-SE reactions are /erZ-alkylation and sulfonylation. 

Kinetic Aspects of Ar-SE Reactions Reactivity and Regioselectivity in Reactions of Electrophiles with Substituted Benzenes... 

Fig. 5.8. Desulfonylation/ resulfonylation as a possibility for isomerizing aromatic sulfonic acids via Ar-SE reactions.

Taking into account the Hammond postulate, this means two things for Ar-SE reactions ... 

Because of completely analogous considerations, every acceptor-substituted sigma complex E—C6H5—EWG is less stable than the reference compound E— C6H6+ (Figure 5.11). From this analysis, one derives the following expectations for Ar-SE reactions of acceptor-substituted benzenes ... 

Substituent Effects on Reactivity and Regioselectivity of Ar-SE Reactions of Monosubstituted Benzenes... 

Therefore, the reactivity and the regioselectivity of Ar-SE reactions with substituted benzenes can be predicted rehably. According to what has been stated above, one only has to iden-... 

Fig. 5.10. Ar-SE reactions with donor-substituted benzenes (Do, donor substituent) comparing the regioselectivity and the reactivity with benzene. The thicknesses of the initial arrows show qualitatively to what extent the reaction takes place via the corresponding transition state.

Reactivity and Regioselectivity in Ar-SE Reactions of Donor-Substituted Aromatic Compounds... 

The regioselectivity and reactivity of Ar-SE reactions of naphthalene are explained correctly by comparing the free activation enthalpies for the formation of the sigma complexes 1- E— C10H10+ and 2-E— E— C10H10+ from the electrophile and naphthalene and for the formation of the sigma complex E— C6H6+ from the electrophile and benzene, respectively. 

Fig. 5.22. Nitration of sulfanilic acid B and desulfonation of the nitration product G. The protonation product D of the substrate is a benzene derivative with two strong electron acceptors (S03H and H3N ) and therefore cannot form a sigma complex under the reacdtion conditions. The fact that an Ar-SE reaction occurs nonetheless is due to the small equilibrium amount of the neutral form B of sulfanilic acid. B is nitrated in ortho-position to the electron donor (H2N) and thus in meta-position to the electron acceptor (S03H).

Fig. 5.23. Mechanism of the nitration of benzene derivatives that are more electron-rich than toluene the sigma complex B is not formed in a single step, as with all other Ar-SE reactions, but in a three-step sequence.

Aryldiazonium salts are weak electrophiles. Consequently, they undergo Ar-SE reactions via sigma complexes (azo couplings) only with the most strongly activated aromatic compounds. Only phenolates and secondary and tertiary aromatic amines react with them. Primary aromatic amines react with diazonium salts, too, but via their N atom. Thus, triazenes, that is, compounds with the structure Ar—N=N—NH—Ar are produced. Phenol ethers or nonde-protonated phenols can react with aryldiazonium salts only when the latter are especially good... 

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