Cowardly. 22.4: Electrophilic aromatic substitution (2023)

scope and mechanism

In this section we are mainly interested in the reactions of arenes that attack the carbon atoms of the aromatic ring. We will not now go into the reactions of the substituent groups around the ring.

The main types of reactions involving aromatic rings are substitution, addition, and oxidation. The most common type of this is electrophilic substitution. An overview of the most important benzene substitution reactions is shown in Figure 22.7. Many of the reagents used for these substitutions are familiar to you in connection with electrophilic addition reactions to alkenes (e.g. \(\ce{Cl_2}\), \(\ce{Br_2}\), \(\ce{ H_2SO_4}\ ) and \(\ce{HOCl}\);§ 10-3). Electrophilic addition to alkenes and electrophilic aromatic substitution are polar step processes, and the key step in each is attack of the electrophile on the carbon to form a cationic intermediate. We can represent this type of reaction by the following general equations, where the attacking reagent is represented either formally as a cation, \(\ce{X}^\ominus\), or as a neutral but polarized molecule, \(\ omitted {\delta \oplus }{\ce{X}}\)---\(\overset{\delta \ominus }{\ce{Y}}\):

electrophilic aromatic substitution(first step)

Elektrophile Addition an Alkene(first step)

The intermediate product presented as an aromatic substitution no longer has an aromatic structure; Rather, it is a cation with four \(\pi\) electrons distributed over five carbon nuclei, with the sixth carbon being saturated with \(sp^3\) hybrid bonds. It can be formulated in terms of the following component structures, which are assumed to make roughly the same contribution:

How important it is to write a hybrid structure with partial charges at these three positions will become clear later. This type of ion is referred to as\(\sigma\) connectionDieBenzolion.

The aromatic ring is regenerated from this cationic intermediate by loss of a proton from the hybridized carbon \(sp^3\). The electron pair in this bond \(\ce{C-H}\) then becomes part of the aromatic \(\pi\)-electron system and a benzene substitution product is formed, \(\ce{C_6H_5X}\).

electrophilic aromatic substitution(second step)

The increase in stabilization associated with the regeneration of the aromatic ring is so favorable that it is usually the preferred course of the reaction and not the combination of the cation with \(\ce{Y}^\ominus\). This is the difference between aromatic substitution and alkene addition. In the case of alkenes, the loss of a proton from an intermediate does not typically yield significant resonance energy, so it tends to react when combined with a nucleophilic reagent.

Elektrophile Addition an Alkene(second step)

\[\overset{\oplus}{\ce{C}} \ce{H_2-CH_2X} + \ce{Y}^\ominus \rightarrow \ce{YCH_2-CH_2X}\]

The type of replacement factor

It is important to know that in aromatic substitution the actual electrophilic substituent \(\overset{\oplus}{\ce{X}}\) or \(\overset{\delta \oplus}{\ce{X } } } } - \overset{\delta \ominus }{\ce{Y}}\) does not necessarily mean the reagent added to the reaction mixture. For example, nitration in mixtures of nitric acid and sulfuric acid is not caused by attack of the nitric acid molecule on the aromatic compound, but by attack of the more electrophilic compound, the nitronium ion, \(\ce{NO_2^+). }\ ). This ion is formed from nitric acid and sulfuric acid according to the following equation:

\[\ce{HNO_3} + 2 \ce{H_2SO_4} \rightleftharpoons \ce{NO_2^+} + \ce{H_3O^+} + 2 \ce{HSO_4^-}\]

The nitronium ion attacks the aromatic ring, producing first the nitrobenzene ion and then the aromatic nitro compound:

In general, the function of the catalyst (so often required to promote aromatic substitution) is to generate an electrophilic substituting agent from the given reagents. Therefore, with each substitution reaction, careful thought must be given to which substitution agent it might actually be. This problem does not arise to the same degree in electrophilic additions to alkenes, since alkenes are so much more reactive than arenes that the reagents used (e.g. \(\ce{Br_2}\), \(\ce{Cl_2}\ ), \(\ce{HCl}\), \(\ce{HOCl}\), \(\ce{HOBr}\), \(\ce{H_3O}^\oplus\)) are sufficiently electrophilic to to react with alkenes without the aid of a catalyst. In fact, conditions that lead to arene substitution, such as nitration in mixtures of nitric and sulfuric acids, often result in degradation of the alkene carbon skeleton.

We now consider each of the substitution reactions shown in Figure 22-1 in terms of the nature of the substituent and its suitability for the synthesis of different classes of aromatic compounds.

nitriding

The nitronium ion, \(\ce{NO_2^+}\), is the active nitrating agent in mixtures of nitric and sulfuric acids. The nitration of methylbenzene (toluene) is a typical example of a nitration that works well with nitric acid in a 1:2 ratio with sulfuric acid. The nitration product is a mixture of 2-, 3- and 4-nitromethylbenzenes:

The presence of significant amounts of water in the reaction mixture is detrimental as water tends to reverse the reaction and generate the nitronium ion:

\[\ce{NO_2^+} + \ce{H_2O} \translated{\ce{HSO_4^-}}{\rightleftharpoons} \ce{HNO_3} + \ce{H_2SO_4}\]

For this reason, the strength of a mixture of nitric and sulfuric acids can be significantly increased by using fuming nitric and fuming sulfuric acids. Nitration of relatively unreactive compounds can be achieved with such mixtures. For example, 4-nitromethylbenzene is much less reactive than methylbenzene, but can be converted sequentially to 2,4-dinitromethylbenzene and 2,4,6-trinitromethylbenzene (TNT) on heating with excess nitric acid in fuming sulfuric acid:

The nitration reactions discussed so far have several interesting features. For example, the conditions required for the nitration of 4-nitromethylbenzene would rapidly oxidize the alkene by cleavage of the double bond:

The mononitration of methylbenzene does not lead to equal amounts of the three possible products either. The methyl substituent appears to orient the introduced substituent preferentially at the 2- and 4-positions. This aspect of aromatic substitution is discussed in§ 22-5combined with the effect of substituents on the reactivity of aromatic compounds.

Some compounds are reactive enough to be nitrated with nitric acid in acetic acid. Suitable examples are 1,3,5-trimethylbenzene and naphthalene:

Other suitable nitrating agents are benzoyl nitrate, \(\ce{C_6H_5COONO_2}\) and ethanoyl nitrate, \(\ce{CH_3COONO_2}\). These reagents are the source of \(\ce{NO_2^+}\) and have some advantages over mixtures of \(\ce{HNO_3} \cdot \ce{H_2SO_4}\) because they are soluble in organic solvents such as ethanonitrile or nitromethane. Homogeneous solutions are particularly important in studies of nitration kinetics. The reactants are usually prepared in solution from the appropriate acyl chloride and silver nitrate, or acid anhydride and nitric acid, as appropriate. Such reagents are hazardous materials and should be handled with care.

Nitrogen salts of the \(\ce{NO_2^+} \ce{X^-}\) type are very strong nitrating agents. The counterion \(\ce{X^-}\) need not be nucleophilic and is typically a fluoroborate, \(\ce{BF_4^-}\) or \(\ce{SbF_4^-}\):

halogenation

We have simplified electrophilic substitution to some extent by neglecting the possible role of the 1:1 charge-transfer complexes that form most electrophiles with arenes (see Fig.Section 10-3Cto discuss analogous complexes of alkenes):

In the case of halogens, especially iodine, the complexation can be visually recognized by the color of the halogen solutions in the arenes. Although complex formation can aid substitution by bringing the halogen and arenium closer together, substitution does not necessarily occur. A catalyst is usually required and the most common catalysts are metal halides that can accept electrons (i.e. Lewis acids such as \(\ce{FeBr_3}\), \(\ce{AlCl_3}\) and \(\ce{ZnCl_2 } \)). Their catalytic activity can be attributed to their ability to polarize the halogen-halogen bond as follows:

\[\overset{\delta \oplus}{\ce{Br}} \cdots \overset{\delta \ominus}{\ce{Br}} \cdots \ce{FeBr_3}\]

The positive end of the dipole attacks the aromatic compound while the negative end becomes complexed with the catalyst. We can represent the reaction sequence as follows, where the slow step is the formation of the \(\sigma\) bond between \(\ce{Br}^\oplus\) and the aromatic ring:

The order of halogen reactivity is: \(\ce{F_2} > \ce{Cl_2} > \ce{Br_2} > \ce{I_2}\). Fluorine is too reactive to be used practically to prepare aromatic fluorine compounds and indirect methods are required (see§ 23-10B). Iodine is usually non-reactive. The iodination has been shown to fail as the reaction is reversed due to the reducing properties of the resulting hydrogen iodide:

\[\ce{C_6H_6} + \ce{I_2} \overset{\rightarrow}{\longleftarrow} \ce{C_6H_5I} + \ce{HI}\]

This view is incorrect since, as Kekule himself has shown, iodobenzene is not reduced by hydroiodic acid except at relatively high temperatures.

One way to achieve direct iodination in the absence of strongly activating substituents is to convert molecular iodine into a more active compound (perhaps \(\ce{H_2OI}^\oplus\) or \(\ce{I}^\oplus\ ).) with an oxidizing agent such as nitric acid or hydrogen peroxide:

\[\begin{align} \ce{I_2} + 4 \ce{HNO_3} &\rightarrow 2 \ce{H_2O-I^+} + 2 \ce{NO_2} + 2 \ce{NO_3^-} \\ \ce{I_2} + \ce{H_2O_2} + 2 \ce{H^+} &\højrepil 2 \ce{H_2OI^+} \end{align}\]

Good yields of iodination products are obtained with such combinations:

Halogen substitution reactions with chlorine or bromine must be carried out with adequate protection from strong light. If such precautions are not taken, aAlkylBenzene reacts rapidly with halogen in a photochemical process, replacing the hydrogen in the alkyl group and not the aromatic ring. The reaction features a light-induced radical chain mechanism as discussed for the chlorination of propene (§ 14-3A). Thus, methylbenzene reacts with bromine on illumination to form phenylmethyl bromide; However, when light is excluded and a Lewis acid catalyst is present, substitution occurs, leading primarily to 2- and 4-bromomethylbenzenes. Significantly less 3-bromomethylbenzene is formed:

Benzene itself can be calledadd to Halogens under strong irradiation to polyhalocyclohexanes (see§§ 21-3AI22-9C):

alkylation

An important method for the synthesis of alkylbenzenes uses an alkyl halide as the alkylating agent and a metal halide, usually aluminum chloride, as the catalyst:

This reaction class is calledFriedel-Crafts Alkylierungin honor of its discoverers C. Friedel (French chemist) and J. M. Crafts (American chemist). The metal halide catalyst works in the same way as halogenation reactions, providing a source of a positive substituent, in this case a carbonic acid:

The alkylation is not limited to alkyl halides; Alcohols and alkenes can advantageously be reacted in the presence of acidic catalysts such as \(\ce{H_3PO_4}\), \(\ce{H_2SO_4}\), \(\ce{HF}\), \(\ce {BF_3} \) or \(\ce{HF-BF_3}\). Ethylbenzene is produced commercially from benzene and ethene using phosphoric acid as a catalyst. Isopropylbenzene is made from benzene and propene in the same way:

Under these conditions, the carbocation, which is the active substitution agent, is formed by protonation of the alkene:

\[\begin{align} \ce{CH_2=CH_2} + \ce{H^+} &\rightleftharpoons \ce{CH_3CH_2^+} \\ \ce{CH_3CH=CH_2} + \ce{H^+} & \rightleftharpoons \ce{CH_3} \overset{+}{\ce{C}} \ce{HCH_3} \end{align}\]

For alcohols, an electrophile can be formed into a carbocation by initial protonation of an acid catalyst and subsequent cleavage:

acylation

Acylation and alkylation of arenes are closely related. Both reactions date back to a collaboration between Friedel and Crafts in 1877. The acylation reaction introduces an acyl group \(\ce{RCO}\) into the aromatic ring and the product is an aryl ketone:

Frequently used acylating reagents are carboxylic acid halides (\ce{RCOCl}\), anhydrides (\(\ce{(RCO)_2O}\) or the acid itself (\(\ce{RCO_2H}\). A strong proton or another Lewis acid is required The catalyst generates an acyl cation:

The most commonly used catalyst with halides and acyl anhydrides is aluminum chloride:

Acylation differs from alkylation in that the reaction is usually carried out in a solvent, usually carbon disulfide, \(\ce{CS_2}\) or nitrobenzene. Acylation also requires more catalyst than alkylation, since much of the catalyst is bound and deactivated by complexation with the keto product:

In contrast to alkylation, acylation can be easily engineered to achieve a single substitution since it is not possible to introduce another acyl group into the same ring once an acyl group is attached to a benzene ring. For this reason, a convenient synthesis of alkylbenzenes begins with acylation, followed by reduction of the carbonyl group with zinc and hydrochloric acid (§ 16-6). For example, propylbenzene is best prepared by this two-step route because, as we have seen, the direct alkylation of benzene with propyl chloride yields significant amounts of isopropylbenzene and polysubstitution products:

The product is almost always formed in the acylation of alkylbenzeneAgainIsomer. Synthese (4-tertThis is illustrated by -butylphenyl)ethanone and the sequential application of the alkylation and acylation reactions:

Chemists tend to give reactions names that associate them either with their discoverers or with the products they make. This practice can be confusing, as many named responses (or "name responses") that were once thought to be entirely unrelated have been shown to have very similar mechanisms. So we have two closely related acylation reactions: one is the Friedel-Crafts ketone synthesis, where the electrophile \(\ce{R} \ce{-} \overset{\oplus}{\ce{C}} \ce { = O } \); and the other isGattermann-Koch aldehyde synthesiswhere the electrophile is \(\ce{H} \ce{-} \overset{\oplus}{\ce{C}} \ce{=O}\):

The latter reaction uses carbon monoxide and \(\ce{HCl}\) under pressure in the presence of aluminum chloride. One can assume that an electrophile is formed as follows:

\[\ce{C=O} + \ce{HCl} + \ce{AlCl_3} \rightleftharpoons \ce{H} \ce{-} \overset{\oplus}{\ce{C}} \ce{= O} + \overset{\ominus}{\ce{Al}} \ce{Cl_4}\]

sulfonation

Substitution of the hydrogen atom in an aromatic hydrocarbon by the sulfonic acid group \(\left( \ce{-SO_3H} \right)\) can be achieved by heating the hydrocarbon with a small excess of concentrated or fuming sulfuric acid:

The actual sulfonating agent is usually the molecule \(\ce{SO_3}\), which is inert but has a strongly electrophilic sulfur atom:

The sulfonation is reversible and the \(\ce{-SO_3H}\) group can be removed by hydrolysis in \(180^\text{o}\):

A sensible alternative production of sulfonyl derivatives is possible with chlorosulfonic acid:

This method has the advantage over direct sulfonation that the sulfonyl chlorides are usually soluble in organic solvents and can be easily separated from the reaction mixture. Sulfonyl chloride is also a more useful intermediate than sulfonic acid, but can be converted to the acid by hydrolysis if necessary:

Sulfonation is important in the commercial manufacture of an important class of detergents, the sodium alkylbenzene sulfonates:

The synthesis illustrates several important types of reactions that we have discussed in this and previous chapters. First, the alkyl group \(\ce{R}\) is usually \(\ce{C_{12}}\) and is derived from the straight-chain hydrocarbon dodecane, which upon photochlorination yields a mixture of chlorododecanes:

This mixture of chlorododecanes is used to alkylate benzene to produce a mixture of isomeric dodecylbenzenesdetergent alkyl:

Sulfonation of a detergent alkylate gives only 4-dodecylbenzene sulfonic acids, which with sodium hydroxide form water-soluble dodecylbenzene sulfonates:

Such cleaning agents, which contain highly branched alkyl groups, are prohibited by law in many countries. This is because quaternary carbon and, to a lesser extent, tertiary carbon are not easily broken down by bacteria in sewage treatment plants:

hydrogen exchange

It is possible to replace hydrogen atoms in the ring of many aromatic compounds by exchange with strong acids. If an isotopically labeled acid such as \(\ce{D_2SO_4}\) is used, this reaction is an easy way to introduce deuterium. The mechanism is analogous to other electrophilic substitutions:

Perdeuteriobenzene \(^3\) can be produced from benzene in good yields when a sufficiently large excess of deuterosulfuric acid is used. Deuteration appears to be competitive with sulfonation, but in fact deuteration takes place under much milder conditions.

Aromatic substitution by electrophilic metalation

Because metals are electropositive elements, they can be considered as potential electrophiles. Their reactions with arenes for mercury have been studied in more detail. Benzene can be replaced by \(\ce{HgX}^\oplus\), a mercury salt derivative, \(\ce{HgX_2}\), in the presence of an acid catalyst. The most commonly used salt is mercury ethoxide, \(\ce{Hg(OOCCH_3)_2}\). The catalyst is believed to act by promoting the production of the active electrophile \(\ce{HgX}^\oplus\). Other metals that can be introduced directly into the aromatic ring in this way are thallium and lead.

\(^3\) prefixTo, as in perdeuterio- or perfluor-, it meansatThe hydrogen atoms were replaced by the mentioned substituent \(\ce{D}\) or \(\ce{F}\). Perhydro means saturated or fully hydrogenated.

Contributors and Attributions

John D. RobertIMarjorie C. A small village(1977)Fundamentals of Organic Chemistry, 2nd Edition.WA Benjamin, Inc., Menlo Park, CA. ISBN 0-8053-8329-8. This content is copyrighted according to the following terms: "Permission is granted for the personal, educational, scholarly, and non-commercial reproduction, distribution, display, and performance of this work in any format."