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ELECTROPHILIC AROMATIC SUBSTITUTION: MECHANISM

Douglas A. Klumpp

Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL, USA

1.1 INTRODUCTION

Electrophilic aromatic substitution (SEAr) is one of the most important synthetic organic reactions [1]. Since its discovery in the 1870s by Charles Friedel and James Crafts [2], it has become a general route to functionalized aromatic compounds. The chemistry is used extensively in the chemical industry, providing millions of tons of aromatic products annually for chemical feedstock, commodity chemicals, and consumer applications. For example, detergents (i.e., 1, Scheme 1.1) are commonly prepared using two SEAr reactions: alkylation and sulfonation. The antibacterial agent sulfadiazine (2) is prepared using nitration and chlorosulfonation reactions during the course of its synthesis, while the disperse dye (3) is prepared using an azo coupling reaction. Several important polymers, such as thermosetting phenol-formaldehyde resins, are also prepared via SEAr reaction steps. In other applications, the chemistry is commonly used in natural product and target-directed syntheses [1].

SCHEME 1.1 Products from SEAr reactions.

In addition to its application in synthetic chemistry, SEAr has one of the most thoroughly studied mechanisms among organic reactions. These studies have paralleled the development of chemistry itself-from the understanding of ions in chemistry and aromaticity in p-systems to the development of high-level theoretical calculations and ultrafast spectroscopic methods. Our understanding of these mechanisms has evolved steadily since the time when the chemistry was first described. This area continues to be an active area of research, and these studies provide new insights into the mechanisms of these valuable organic transformations. The importance of this mechanistic understanding cannot be overstated. Because the chemistry has significant economic value, mechanistic understanding is crucial for chemists to maximize reaction yields, reduce costs, and minimize the environmental impacts of these synthetic processes. In the following chapter, I will provide an overview of the SEAr reaction mechanism, discussing the salient features of these processes and efforts to understand them.

1.2 GENERAL ASPECTS

The SEAr reactions involve more than 20 distinctly different types of substitutions, yet these transformations have similar overall mechanisms. The commonly proposed mechanism involves interaction of an electrophilic species with the p-system of an arene (Scheme 1.2) [3]. The electrophile (E+) itself is often a cationic species (vide infra), but SEAr reactions may also be initiated by dipolar groups or molecules. The initial interaction may lead to the formation of a p-complex or an encounter complex. The p-complex often forms the s-complex intermediate, also known as the Wheland complex. In the final step, a base removes the ipso proton and the substitution product is obtained. This mechanistic interpretation also allows for the formation of a second p-complex from the s-complex intermediate, where the proton is loosely bound to the p-system. With the regeneration of the aromatic p-system, product stability typically leads to a fast reaction in the final step.

SCHEME 1.2 Proposed mechanism for the SEAr reaction.

There are several variations of this mechanism. For example, in nitrations, there is considerable evidence to suggest single electron transfer between the nitronium cation (NO2+) and the arene (vide infra), followed by coupling of the product radicals to give a s-complex intermediate [4]. There are also examples known involving addition of radical species into the arene (such as ·NO2) as a route to substitution products [5]. Moreover, there are examples of SEAr reactions in which (cationic) groups other than H+ leave the final reaction step [6].

1.3 ELECTROPHILES

The electrophiles in SEAr reactions may be divided into two basic categories: those with fully formed cationic charge centers and those having reactive, polarized bonds. For example, Friedel-Crafts alkylation often occurs through the involvement of discrete carbocation intermediates (see Chapter 2).

This may be contrasted with the D2SO4-promoted hydrogen-deuterium exchange at an arene (Eq. 1.1). In this case, the electrophilic chemistry occurs at the polarized deuterium-oxygen bond, where the deuterium atom carries a significant positive charge. Although the various SEAr synthetic reactions do share a common basic mechanism (Scheme 1.2), they often differ considerably in the means or mechanisms by which the electrophiles are generated. Several of the common mechanistic types are described below.

Many electrophilic species are generated by the action of Lewis acid catalysts. For example, Friedel-Crafts acylation may occur through the involvement of the acylium ion (i.e., 4) often generated by Lewis acid-promoted halide abstraction (Eq. 1.2) [7]. Similar Lewis acid-promoted reactions may be used to give carbocationic species from alkyl halides, carboxonium ions from acetals and related precursors, iminium ions from a-haloalkylamines, and others.

While discrete cationic species may be formed by Lewis acid reactions, highly polarized species may also be the active electrophiles in the transformations. In the case of brominations (Scheme 1.3), Br2 itself may develop a small dipole (5) with approach to an electron-rich arene (such as phenol). Interaction with the Lewis acid may increase the degree of polarization (6) or, in the limiting case, give the bromonium ion (7). The exact nature of the reacting electrophile depends on several factors, including the reactivity of the arene nucleophile, temperature, strength of the Lewis acid, or solvent ionizing power.

SCHEME 1.3 The development of cationic charge on bromine.

In the case of Brønsted acid catalysts, cationic electrophiles may be generated by the direct protonation of a functional group (Fig. 1.1). This type of chemistry is especially important in the SEAr reactions of carbonyl compounds and olefins. The carboxonium ions (8 and 9) and nitrilium ion (10) are formed by protonation at a nonbonding electron pair, while protonation at the olefinic p-bond gives the carbocation (11). Both solid (i.e., zeolites) and liquid Brønsted acids may generate electrophiles by this chemistry.

FIGURE 1.1 Examples of electrophiles formed by direct protonation.

In many types of SEAr reactions, cationic electrophile formation requires one or more steps after functional group protonation or activation (Fig. 1.2). Alcohols and related functional groups are protonated, and with subsequent cleavage of CO bond, the carbocation electrophile (11) is formed. In a similar respect, a common method of nitration involves the use of HNO3 with H2SO4. The nitronium ion electrophile (NO2+, 12) is formed by protonation of nitric acid and subsequent loss of water by cleavage of the NO bond [8]. The nitrosonium ion electrophile (NO+) may be generated by an analogous transformation from nitrous acid, HNO2 [9]. Likewise, N-acyliminium ion electrophiles (i.e., 13) may be formed by ionization of N-hydroxymethylamides [10].

FIGURE 1.2 Electrophiles generated from Brønsted acids.

There are many examples of Brønsted acid-promoted reactions where highly polarized functional groups are the active electrophiles. For example, Olah and coworkers reported N-chlorosuccinimide to be a powerful chlorinating agent with superacidic BF3H2O [11]. The active electrophile is likely the diprotonated (14) or triprotonated species (15, Eq. 1.3),

which transfers Cl+ directly to the arene nucleophile. This system is capable of chlorinating nitrobenzene-a strongly deactivated arene-in 69% yield. In SEAr reactions with epoxides, the CO bond may undergo nucleophilic ring opening following protonation or strong hydrogen bonding at the oxygen. Thus, the epoxide substrate (16) provides the cyclialkylation product (17) in quantitative yield by the action of 1,1,1,3,3,3-hexafluoroisopropanol (Scheme 1.4) [12]. It is suggested that the epoxide is protonated (or coordinated through hydrogen bonding), leading to a nucleophilic ring opening of the epoxide.

SCHEME 1.4 An intramolecular SEAr reaction with epoxide 16.

There are numerous multistep processes that generate electrophiles. As examples of these types of reactions, we will consider the diazotization of anilines and the formation of chloroiminium ions in the Vilsmeier-Haack reaction. Aryl diazonium ions are useful in the modification of arenes by the Sandmeyer reaction and as electrophilic intermediates in diazonium coupling reactions for the synthesis of dyes and pigments. Several types of synthetic methods have been developed for...