Electrophilic aromatic substitution

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.

Contents [hide] 1 Basic reactions 2 Other reactions 3 Basic reaction mechanism 4 Substituted aromatic rings 4.1 Ortho/para directors 4.2 Meta directors 5 Ipso substitution 6 Five membered heterocyclic compounds 7 Asymmetric electrophilic aromatic substitution 8 External links 9 References

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[edit]
Basic reactions


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





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





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





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





The catalyst is most typically aluminium trichloride,
but almost any strong Lewis acid can be used.
In Friedel-Crafts acylation, a full measure of aluminium trichloride must be
used, as opposed to a catalytic amount.





[edit]
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.
  
• In the Tscherniac-Einhorn
  reaction (named after Alfred Einhorn) the electrophile is a
  N-methanol derivative of an amide ^[1]
  

[edit]
Basic reaction mechanism


In the first step of the reaction mechanism
for this reaction, the electron-rich aromatic ring which in the simplest case
is benzene attacks the electrophile A. 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 the second stage of the reaction, a Lewis base B donates electrons to the
0909 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.


[edit]
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 and para 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.


[edit]
Ortho/para directors


0909 pairs[/url]
of electrons, such as the amino group of aniline, are strongly activating and ortho/para-directing.
Such activating groups
0909 electrons to the pi system.





When the electrophile attacks the ortho
and para
positions of aniline, the nitrogen atom can donate
electron density to the pi system (forming an iminium ion), 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 that 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
0909 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.


Halogens are ortho/para
0909 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.


[edit] Meta
directors


Non-halogen groups with atoms that are more electronegative
than carbon, such as a carboxilic acid group (CO₂H) 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. -CF₃, -CCl₃, -CBr₃,
-CI₃ are meta directors.


[edit]
Ipso substitution


Ipso substitution 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. See also Hayashi rearrangement.


In aromatics substituted by silicon, the silicon reacts by
ipso substitution.


[edit] 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
0909 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.


[edit] 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 aluminium chloride
modified with (-)-menthol ^[2]. 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 ^[3]:





In another alkylation N-methylpryrrole reacts with crotonaldehyde catalyzed by trifluoroacetic acid
modified with a chiral imidazolidinone ^[4]:





Indole reacts with an enamide
catalyzed by a chiral BINOL derived phosphoric acid ^[5]:





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.

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