View source for Electrophilic aromatic substitution

'''Electrophilic aromatic substitution''' or '''EAS''' is an [[organic reaction]] in which an atom, usually [[hydrogen]], appended to an [[aromatic ring|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 reaction]]s.

== Basic reactions ==
[[Aromatic nitration]]s to form [[nitro compound]]s take place by generating a nitronium ion from [[nitric acid]] and [[sulfuric acid]].

:[[Image:BenzeneNitration.png|Nitration of Benzene]]

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

:[[Image:BenzeneSulfonation.png|Sulfonation of Benzene]]

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

:[[Image:BenzeneHalogenation.png|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]]. 

:[[Image:BenzeneFriedelCraftsAcylation.png|Friedel-Crafts Acylation with acyl chloride]]

The catalyst is always [[aluminium chloride]].

:[[Image:BenzeneFriedelCraftsAlkylation.png|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 salt]]s in [[diazonium coupling]]s, [[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 (chemistry)|resonance]], which allows the positive charge to be distributed over three carbon atoms.

:[[Image:EAS Mechanism.png|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 group]]s. 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 [[aromatic ipso position|ipso]], the next ring atom is position 2 or [[Aromatic ortho substituent|ortho]], position 3 is [[Aromatic meta substituent|meta]] and position 4 is [[Aromatic para substituent|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 group]]s stabilize the cationic intermediate formed during the substitution by donating electrons into the ring system, by either [[inductive effect]] or [[resonance effect]]s.  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 groups|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 [[free electron pair|unshared pairs]] of electrons, such as the [[amino]] group of [[aniline]], are strongly ''activating'' and ''ortho/para''-directing.  Such [[activating group]]s donate those unshared electrons to the ''pi'' system.

:[[Image:EAS substitutionPatterns.png|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 structure]]s (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]] [[substituent]]s, 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.
:[[Image:EAS MetaSubstitution.png|resonance structures for meta attack of an electrophile on aniline]]

[[Halogen]]s 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 group]]s.

[[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 (NO<sub>2</sub>) 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 acid|nitric]] and [[sulfuric acid]] to form picric acid. The nitration of the 2 position involves the loss of CO<sub>2</sub> 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 reaction|friedel-Crafts type reactions]]. An early example concerns the addition of [[chloral]] to [[phenols]] catalyzed by [[aluminum chloride]] modified with [[menthol|(-)-menthol]] <ref>''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</ref>. A [[Glyoxylate]] compound has been added to [[Dimethylaniline|N,N-dimethylaniline]] with a chiral [[bisoxazoline ligand]] - [[copper(II) triflate]] catalyst system also in a [[Friedel-Crafts hydroxyalkylation]] <ref>''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}}</ref>:

:[[Image:FriedelcraftsAlkylationAsymmetric.png|350px|Asymmetric Friedel-Crafts hydroxyalkylation ]]

In another alkylation [[Pyrrole|N-methylpryrrole]] reacts with [[crotonaldehyde]] catalyzed by [[trifluoroacetic acid]] modified with a chiral [[imidazole|imidazolidinone]] <ref>''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}}</ref>:

:[[Image:FriedelCraftsAsymmetricAdditionToPyrrole.png|350px|Friedel Crafts Asymmetric Addition To Pyrrole]]

[[Indole]] reacts with an [[enamide]] catalyzed by a chiral [[BINOL]] derived [[phosphoric acid]] <ref>''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}}</ref>:

:[[Image:FriedelCraftsAlkylationIndoleAsymmetric.png|350px|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 [[enantiomeric excess|ee]].

==External links==
* [http://www.cem.msu.edu/~reusch/VirtTxtJml/benzrx1.htm Aromatic Substitution Reactions - MSU]

==References==
{{reflist|2}}

[[Category:Substitution reactions]]

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