Electrophilic aromatic substitution

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Electrophilic aromatic substitution (SEAr) is an

aromatic halogenation, aromatic sulfonation, alkylation and acylation Friedel–Crafts reaction.[1]

Illustrative reactions

The most widely practised example of this reaction is the ethylation of benzene.

Approximately 24,700,000 tons were produced in 1999.

Aromatic halogenation with bromine, chlorine, or iodine
gives the corresponding aryl halides. This reaction is typically catalyzed by the corresponding iron or aluminum trihalide.

The

stoichiometric
amount of aluminum trichloride is required.

Reaction mechanism

The overall reaction mechanism, denoted by the

cation, also known as an arenium ion, Wheland intermediate, or arene σ-complex (2b). Many examples of this carbocation
have been characterized, but under normal operating conditions these highly acidic species will donate the proton attached to the sp3 carbon to the solvent (or any other weak base) to reestablish aromaticity. The net result is the replacement of H by E in the aryl ring (3).

Occasionally, other electrofuges (groups that can leave without their electron pair) beside H+ will depart to reestablish aromaticity; these species include silyl groups (as SiR3+), the carboxy group (as CO2 + H+), the iodo group (as I+), and tertiary alkyl groups like t-butyl (as R+). The capacity of these types of substituents to leave is sometimes exploited synthetically, particularly the case of replacement of silyl by another functional group (ipso attack). However, the loss of groups like iodo or alkyl is more often an undesired side reaction.

Reaction mechanism for electrophilic aromatic substitution

Effect of substituent groups

Main article: Electrophilic aromatic directing groups
Diagram showing the ortho, meta and para positions relative to a substituent X on a benzene ring

Both the

para positions, whereas other groups favor substitution at the meta position. These groups are called either ortho–para directing or meta directing, respectively. In addition, some groups will increase the rate of reaction (activating) while others will decrease the rate (deactivating). While the patterns of regioselectivity can be explained with resonance structures, the influence on kinetics can be explained by both resonance structures and the inductive effect
.

Reaction rate

Substituents can generally be divided into two classes regarding electrophilic substitution: activating and deactivating towards the aromatic ring. Activating substituents 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 distributed evenly over the entire ring but is concentrated on atoms 2, 4 and 6, so activating substituents are also ortho/para directors (see below).

On the other hand,

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. Groups that are electron-withdrawing by resonance decrease the electron density especially at positions 2, 4 and 6, leaving positions 3 and 5 as the ones with comparably higher reactivity, so these types of groups are meta directors (see below). Halogens
are electronegative, so they are deactivating by induction, but they have lone pairs, so they are resonance donors and therefore ortho/para directors.

Ortho/para directors

Groups with

steric hindrance
between activating group and electrophile but on the other hand there are two ortho positions for reaction but only one para position. Hence the final outcome of the electrophilic aromatic substitution is difficult to predict, and it is usually only established by doing the reaction and observing the ratio of ortho versus para substitution.

resonance structures for ortho attack of an electrophile on aniline
resonance structures for ortho attack of an electrophile on aniline

In addition to the increased nucleophilic nature of the original ring, when the electrophile attacks the ortho and para positions of aniline, the

resonance structures
(as opposed to three in the basic reaction). This substantially enhances the stability of the cationic intermediate.

Resonance structures for para attack
Resonance structures for para attack

When the electrophile attacks the meta position, the nitrogen atom cannot donate electron density to the pi system, giving only three resonance contributors. This reasoning is consistent with low yields of meta-substituted product.

resonance structures for meta attack of an electrophile on aniline
resonance structures for meta attack of an electrophile on aniline

Other substituents, such as the

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.

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 a carboxylic acid group (-CO2H), withdraw substantial electron density from the pi system. These groups are strongly

deactivating groups
. Additionally, since the substituted carbon is already electron-poor, any structure having a resonance contributor in which there is a positive charge on the carbon bearing the electron-withdrawing group (i.e., ortho or para attack) is less stable than the others. Therefore, these electron-withdrawing groups are meta directing because this is the position that does not have as much destabilization.

The reaction is also much slower (a relative reaction rate of 6×10−8 compared to benzene) because the ring is less nucleophilic.

Reaction on pyridine

Compared to benzene, the rate of electrophilic substitution on pyridine is much slower, due to the higher electronegativity of the nitrogen atom. Additionally, the nitrogen in pyridine easily gets a positive charge either by protonation (from nitration or sulfonation) or Lewis acids (such as AlCl3) used to catalyze the reaction. This makes the reaction even slower by having adjacent formal charges on carbon and nitrogen or 2 formal charges on a localised atom. Doing an electrophilic substitution directly in pyridine is nearly impossible.

In order to do the reaction, they can be made by 2 possible reactions, which are both indirect.

One possible way to do a substitution on pyridine is nucleophilic aromatic substitution. Even with no catalysts, the nitrogen atom, being electronegative, can hold the negative charge by itself. Another way is to do an oxidation before the electrophilic substitution. This makes pyridine N-oxide, which due to the negative oxygen atom, makes the reaction faster than pyridine, and even benzene. The oxide then can be reduced to the substituted pyridine.

Ipso attack

The attachment of an entering group to a position in an aromatic compound already carrying a substituent group (other than hydrogen). The entering group may displace that substituent group but may also itself be expelled or migrate to another position in a subsequent step. The term 'ipso-substitution' is not used, since it is synonymous with substitution.[4] 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.

Five membered heterocycles

Compared to benzene, furans, thiophenes, and pyrroles are more susceptible to electrophilic attack. 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 stabilizes 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

Friedel–Crafts hydroxyalkylation:[6]

Asymmetric Friedel–Crafts hydroxyalkylation
Asymmetric Friedel–Crafts hydroxyalkylation

In another alkylation N-methylpyrrole reacts with crotonaldehyde catalyzed by trifluoroacetic acid modified with a chiral imidazolidinone:[7]

Friedel Crafts Asymmetric Addition To Pyrrole
Friedel Crafts Asymmetric Addition To Pyrrole

BINOL derived phosphoric acid:[8]

Friedel Crafts Alkylation Indole Asymmetric
Friedel Crafts Alkylation Indole Asymmetric

In the presence of 10–20 % chiral catalyst, 80–90% ee is achievable.

Other reactions

See also

References

  1. ISBN 978-0-471-72091-1
  2. doi:10.1002/14356007.a10_035.pub2
  3. ISSN 0040-4039
    .
  4. doi:10.1351/goldbook.I03251
  5. doi:10.1021/jo00225a003
  6. doi:10.1021/ja002593j
  7. doi:10.1021/ja015717g
  8. doi:10.1002/anie.200701067
  9. ^ Verfahren zur Darstellung von Benzylphtalimiden Joseph Tscherniac German Patent 1902, DE-134,979
  10. doi:10.1002/jlac.19053430207

External links
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