Electrophilic aromatic substitution

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Electrophilic aromatic substitution or EAS is an organic reaction in which an atom, usually hydrogen, appended to an aromatic system is replaced by an electrophile. The most important reactions of this type that take place are aromatic nitration, aromatic halogenation, aromatic sulfonation, and acylation and alkylating Friedel-Crafts reactions.

Basic reactions

Aromatic nitrations to form nitro compounds take place by generating a nitronium ion from nitric acid and sulfuric acid.

Nitration of Benzene

Aromatic sulfonation of benzene with fuming sulfuric acid gives benzenesulfonic acid.

Sulfonation of Benzene

Aromatic halogenation of benzene with bromine, chlorine or iodine gives the corresponding aryl halogen compounds catalyzed by iron tribromide.

Halogenation of Benzene, X = Br, Cl, I

The Friedel-Crafts reaction exists as an acylation and an alkylation with as reactants acyl halides or alkyl halides.

Friedel-Crafts Acylation with acyl chloride

The catalyst is always aluminium chloride.

Friedel-Crafts Alkylation with an alkyl chloride

Other reactions

Other reactions that follow an electrophilic aromatic substitution pattern are a group of aromatic formylation reactions including the Vilsmeier-Haack reaction, the Gattermann Koch reaction and the Reimer-Tiemann reaction. Other electrophiles are aromatic diazonium salts in diazonium couplings, carbon dioxide in the Kolbe-Schmitt reaction and activated carbonyl groups in the Pechmann condensation.

In the multistep Lehmstedt-Tanasescu reaction, one of the electrophiles is a N-nitroso intermediate.

Basic reaction mechanism

In the first step of the reaction mechanism for this reaction, the electrophile A is attacked by the electron-rich aromatic ring which in the simplest case is benzene. This leads to the formation of a positively-charged cyclohexadienyl cation, also known as an arenium ion. This carbocation is unstable, owing both to the positive charge on the molecule and to the temporary loss of aromaticity. However, the cyclohexadienyl cation is partially stabilized by resonance, which allows the positive charge to be distributed over three carbon atoms.

In this diagram, A+ is an arbitrary electrophile


In the second stage of the reaction, a Lewis base B donates electrons to the hydrogen atom at the point of electrophilic attack, and the electrons shared by the hydrogen return to the pi system, restoring aromaticity.

An electrophilic substitution reaction on benzene does not always result in monosubstitution. While electrophilic substituents usually withdraw electrons from the aromatic ring and thus deactivate it against further reaction, a sufficiently strong electrophile can perform a second or even a third substitution. This is especially the case with the use of catalysts.

Substituted aromatic rings

Electrophiles may attack aromatic rings with functional groups. Performing an electrophilic substitution on an already substituted benzene compound raises the problem of regioselectivity. In case of a monosubstituted benzene, there are 4 different reactive positions. For a monosubstituted benzene, the ring carbon atom bearing the substituent is position 1 or ipso, the next ring atom is position 2 or ortho, position 3 is meta and position 4 is para. Positions 5 and 6 are respectively equal to 3 and 2.

Substituents can generally be divided into two classes regarding electrophilic substitution: activating and deactivating towards the aromatic ring. Activating substituents or activating groups stabilize the cationic intermediate formed during the substitution by donating electrons into the ring system, by either inductive effect or resonance effects. Examples of activated aromatic rings are toluene, aniline and phenol.

The extra electron density delivered into the ring by the substituent is not equally divided over the entire ring, but is concentrated on atoms 2, 4 and 6 (the ortho and para positions). These positions are thus the most reactive towards an electron-poor electrophile. The highest electron density is located on both ortho positions, though this increased reactivity might be offset by steric hindrance between substituent and electrophile. The final result of the elecrophilic aromatic substitution might thus be hard to predict, and it is usually only established by doing the reaction and determining the ratio of ortho versus para substitution.

On the other hand, deactivating substituents destabilize the intermediate cation and thus decrease the reaction rate. They do so by withdrawing electron density from the aromatic ring, though the positions most affected are again the ortho and para ones. This means that the most reactive positions (or, least unreactive) are the meta ones (atoms 3 and 5). Examples of deactivated aromatic rings are nitrobenzene, benzaldehyde and trifluoromethylbenzene. The deactivation of the aromatic system also means that generally harsher conditions are required to drive the reaction to completion. An example of this is the nitration of toluene during the production of trinitrotoluene (TNT). While the first nitration, on the activated toluene ring, can be done at room temperature and with dilute acid, the second one, on the deactivated nitrotoluene ring, already needs prolonged heating and more concentrated acid, and the third one, on very strongly deactivated dinitrotoluene, has to be done in boiling concentrated sulfuric acid.

Functional groups thus usually tend to favor one or two of these positions above the others; that is, they direct the electrophile to specific positions. A functional group that tends to direct attacking electrophiles to the meta position, for example, is said to be meta-directing.

Ortho/para directors

Groups with unshared pairs of electrons, such as the amino group of aniline, are strongly activating and ortho/para-directing. Such activating groups donate those unshared electrons to the pi system.

resonance structures for ortho attack of an electrophile on aniline

When the electrophile attacks the ortho and para positions of aniline, the nitrogen atom can donate electron density to the pi system, giving four resonance structures (as opposed to three in the basic reaction). This substantially enhances the stability of the cationic intermediate. Compare this with the case when the electrophile attacks the meta position.


In this case, the nitrogen atom cannot donate electron density to the pi system, giving only three resonance contributors. For this reason, the meta-substituted product is produced in much smaller proportion to the ortho and para products.

Other substituents, such as the alkyl and aryl substituents, may also donate electron density to the pi system; however, since they lack an available unshared pair of electrons, their ability to do this is rather limited. Thus they only weakly activate the ring and do not strongly disfavor the meta position.

resonance structures for meta attack of an electrophile on aniline

Halogens are ortho/para directors, since they possess an unshared pair of electrons just as nitrogen does. However, the stability this provides is offset by the fact that halogens are substantially more electronegative than carbon, and thus draw electron density away from the pi system. This destabilizes the cationic intermediate, and EAS occurs less readily. Halogens are therefore deactivating groups.

Directed ortho metalation is a special type of EAS with special ortho directors.

Meta directors

Non-halogen groups with atoms that are more electronegative than carbon, such as the nitro group (NO2) draw substantial electron density from the pi system. These groups are strongly deactivating groups. Additionally, since the substituted carbon is already electron-poor, the resonance contributor with a positive charge on this carbon (produced by ortho/para attack) is less stable than the others. Therefore, these electron-withdrawing groups are meta directors.

Ipso substitution

Ipso substitution is a special case of electrophilic aromatic substitution where the leaving group is not hydrogen.

A classic example is the reaction of salicylic acid with a mixture of nitric and sulfuric acid to form picric acid. The nitration of the 2 position involves the loss of CO2 as the leaving group.

Desulfonation in which a sulfonyl group is substituted by a proton is a common example.

Five membered heterocyclic compounds

Furan, Thiophene, Pyrrole and their derivatives are all highly activated compared to benzene. These compounds all contain an atom with an unshared pair of electrons (oxygen, sulfur, or nitrogen) as a member of the aromatic ring, which substantially increases the stability of the cationic intermediate. Examples of electrophilic substitutions to pyrrole are the Pictet-Spengler reaction and the Bischler-Napieralski reaction.

Asymmetric electrophilic aromatic substitution

Electrophilic aromatic substitutions with prochiral carbon electrophiles have been adapted for asymmetric synthesis by switching to chiral lewis acid catalysts especially in friedel-Crafts type reactions. An early example concerns the addition of chloral to phenols catalyzed by aluminum chloride modified with (-)-menthol [1]. A Glyoxylate compound has been added to N,N-dimethylaniline with a chiral bisoxazoline ligand - copper(II) triflate catalyst system also in a Friedel-Crafts hydroxyalkylation [2]:

Asymmetric Friedel-Crafts hydroxyalkylation

In another alkylation N-methylpryrrole reacts with crotonaldehyde catalyzed by trifluoroacetic acid modified with a chiral imidazolidinone [3]:

Friedel Crafts Asymmetric Addition To Pyrrole

Indole reacts with an enamide catalyzed by a chiral BINOL derived phosphoric acid [4]:

Friedel Crafts Alkylation Indole Asymmetric

In all these reactions the chiral catalyst load is between 10 to 20% and a new chiral carbon center is formed with 80-90 ee.

External links

References

  1. Asymmetric electrophilic substitution on phenols in a Friedel-Crafts hydroxyalkylation. Enantioselective ortho-hydroxyalkylation mediated by chiral alkoxyaluminum chlorides Franca Bigi, Giovanni Casiraghi, Giuseppe Casnati, Giovanni Sartori, Giovanna Gasparri Fava, and Marisa Ferrari Belicchi J. Org. Chem.; 1985; 50(25) pp 5018 - 5022; DOI: 10.1021/jo00225a003
  2. Catalytic Enantioselective Friedel-Crafts Reactions of Aromatic Compounds with Glyoxylate: A Simple Procedure for the Synthesis of Optically Active Aromatic Mandelic Acid Esters Nicholas Gathergood, Wei Zhuang, and Karl Anker Jrgensen J. Am. Chem. Soc.; 2000; 122(50) pp 12517 - 12522; (Article) doi:10.1021/ja002593j
  3. New Strategies in Organic Catalysis: The First Enantioselective Organocatalytic Friedel-Crafts Alkylation Nick A. Paras and David W. C. MacMillan J. Am. Chem. Soc.; 2001; 123(18) pp 4370 - 4371; (Communication) doi:10.1021/ja015717g
  4. Chiral Brønsted Acid Catalyzed Enantioselective Friedel–Crafts Reaction of Indoles and a-Aryl Enamides: Construction of Quaternary Carbon Atoms Yi-Xia Jia, Jun Zhong, Shou-Fei Zhu, Can-Ming Zhang, and Qi-Lin Zhou Angew. Chem. Int. Ed. 2007, 46, 5565 –5567 doi:10.1002/anie.200701067

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