Electrophilic aromatic substitution
Overview
 
Electrophilic aromatic substitution EAS is an organic reaction
Organic reaction
Organic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, photochemical reactions and redox reactions. In organic synthesis,...

 in which an atom, usually hydrogen
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...

, appended to an aromatic system is replaced by an electrophile
Electrophile
In general electrophiles are positively charged species that are attracted to an electron rich centre. In chemistry, an electrophile is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile...

. The most important reactions of this type that take place are aromatic nitration, aromatic halogenation, aromatic sulfonation
Aromatic sulfonation
Aromatic sulfonation is an organic reaction in which a hydrogen atom on an arene is replaced by a sulfonic acid functional group in an electrophilic aromatic substitution.-Mechanism:...

, and acylation and alkylating Friedel–Crafts reactions.
Aromatic nitrations to form nitro compound
Nitro compound
Nitro compounds are organic compounds that contain one or more nitro functional groups . They are often highly explosive, especially when the compound contains more than one nitro group and is impure. The nitro group is one of the most common explosophores used globally...

s take place by generating a nitronium ion from nitric acid
Nitric acid
Nitric acid , also known as aqua fortis and spirit of nitre, is a highly corrosive and toxic strong acid.Colorless when pure, older samples tend to acquire a yellow cast due to the accumulation of oxides of nitrogen. If the solution contains more than 86% nitric acid, it is referred to as fuming...

 and sulfuric acid
Sulfuric acid
Sulfuric acid is a strong mineral acid with the molecular formula . Its historical name is oil of vitriol. Pure sulfuric acid is a highly corrosive, colorless, viscous liquid. The salts of sulfuric acid are called sulfates...

.


Aromatic sulfonation
Aromatic sulfonation
Aromatic sulfonation is an organic reaction in which a hydrogen atom on an arene is replaced by a sulfonic acid functional group in an electrophilic aromatic substitution.-Mechanism:...

 of benzene
Benzene
Benzene is an organic chemical compound. It is composed of 6 carbon atoms in a ring, with 1 hydrogen atom attached to each carbon atom, with the molecular formula C6H6....

 with fuming sulfuric acid
Sulfuric acid
Sulfuric acid is a strong mineral acid with the molecular formula . Its historical name is oil of vitriol. Pure sulfuric acid is a highly corrosive, colorless, viscous liquid. The salts of sulfuric acid are called sulfates...

 gives benzenesulfonic acid.


Aromatic halogenation of benzene with bromine
Bromine
Bromine ") is a chemical element with the symbol Br, an atomic number of 35, and an atomic mass of 79.904. It is in the halogen element group. The element was isolated independently by two chemists, Carl Jacob Löwig and Antoine Jerome Balard, in 1825–1826...

, chlorine
Chlorine
Chlorine is the chemical element with atomic number 17 and symbol Cl. It is the second lightest halogen, found in the periodic table in group 17. The element forms diatomic molecules under standard conditions, called dichlorine...

 or iodine
Iodine
Iodine is a chemical element with the symbol I and atomic number 53. The name is pronounced , , or . The name is from the , meaning violet or purple, due to the color of elemental iodine vapor....

 gives the corresponding aryl halogen compounds catalyzed by the corresponding iron trihalide.


The Friedel-Crafts reaction
Friedel-Crafts reaction
The Friedel–Crafts reactions are a set of reactions developed by Charles Friedel and James Crafts in 1877. There are two main types of Friedel–Crafts reactions: alkylation reactions and acylation reactions. This reaction type is a form of electrophilic aromatic substitution...

 exists as an acylation
Acylation
In chemistry, acylation is the process of adding an acyl group to a compound. The compound providing the acyl group is called the acylating agent....

 and an alkylation
Alkylation
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion or a carbene . Alkylating agents are widely used in chemistry because the alkyl group is probably the most common group encountered in...

 with acyl halides or alkyl halides as reactants.


The catalyst is most typically aluminium trichloride, but almost any strong Lewis acid
Lewis acid
]The term Lewis acid refers to a definition of acid published by Gilbert N. Lewis in 1923, specifically: An acid substance is one which can employ a lone pair from another molecule in completing the stable group of one of its own atoms. Thus, H+ is a Lewis acid, since it can accept a lone pair,...

 can be used.
Encyclopedia
Electrophilic aromatic substitution EAS is an organic reaction
Organic reaction
Organic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, photochemical reactions and redox reactions. In organic synthesis,...

 in which an atom, usually hydrogen
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...

, appended to an aromatic system is replaced by an electrophile
Electrophile
In general electrophiles are positively charged species that are attracted to an electron rich centre. In chemistry, an electrophile is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile...

. The most important reactions of this type that take place are aromatic nitration, aromatic halogenation, aromatic sulfonation
Aromatic sulfonation
Aromatic sulfonation is an organic reaction in which a hydrogen atom on an arene is replaced by a sulfonic acid functional group in an electrophilic aromatic substitution.-Mechanism:...

, and acylation and alkylating Friedel–Crafts reactions.

Basic reactions

Aromatic nitrations to form nitro compound
Nitro compound
Nitro compounds are organic compounds that contain one or more nitro functional groups . They are often highly explosive, especially when the compound contains more than one nitro group and is impure. The nitro group is one of the most common explosophores used globally...

s take place by generating a nitronium ion from nitric acid
Nitric acid
Nitric acid , also known as aqua fortis and spirit of nitre, is a highly corrosive and toxic strong acid.Colorless when pure, older samples tend to acquire a yellow cast due to the accumulation of oxides of nitrogen. If the solution contains more than 86% nitric acid, it is referred to as fuming...

 and sulfuric acid
Sulfuric acid
Sulfuric acid is a strong mineral acid with the molecular formula . Its historical name is oil of vitriol. Pure sulfuric acid is a highly corrosive, colorless, viscous liquid. The salts of sulfuric acid are called sulfates...

.


Aromatic sulfonation
Aromatic sulfonation
Aromatic sulfonation is an organic reaction in which a hydrogen atom on an arene is replaced by a sulfonic acid functional group in an electrophilic aromatic substitution.-Mechanism:...

 of benzene
Benzene
Benzene is an organic chemical compound. It is composed of 6 carbon atoms in a ring, with 1 hydrogen atom attached to each carbon atom, with the molecular formula C6H6....

 with fuming sulfuric acid
Sulfuric acid
Sulfuric acid is a strong mineral acid with the molecular formula . Its historical name is oil of vitriol. Pure sulfuric acid is a highly corrosive, colorless, viscous liquid. The salts of sulfuric acid are called sulfates...

 gives benzenesulfonic acid.


Aromatic halogenation of benzene with bromine
Bromine
Bromine ") is a chemical element with the symbol Br, an atomic number of 35, and an atomic mass of 79.904. It is in the halogen element group. The element was isolated independently by two chemists, Carl Jacob Löwig and Antoine Jerome Balard, in 1825–1826...

, chlorine
Chlorine
Chlorine is the chemical element with atomic number 17 and symbol Cl. It is the second lightest halogen, found in the periodic table in group 17. The element forms diatomic molecules under standard conditions, called dichlorine...

 or iodine
Iodine
Iodine is a chemical element with the symbol I and atomic number 53. The name is pronounced , , or . The name is from the , meaning violet or purple, due to the color of elemental iodine vapor....

 gives the corresponding aryl halogen compounds catalyzed by the corresponding iron trihalide.


The Friedel-Crafts reaction
Friedel-Crafts reaction
The Friedel–Crafts reactions are a set of reactions developed by Charles Friedel and James Crafts in 1877. There are two main types of Friedel–Crafts reactions: alkylation reactions and acylation reactions. This reaction type is a form of electrophilic aromatic substitution...

 exists as an acylation
Acylation
In chemistry, acylation is the process of adding an acyl group to a compound. The compound providing the acyl group is called the acylating agent....

 and an alkylation
Alkylation
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion or a carbene . Alkylating agents are widely used in chemistry because the alkyl group is probably the most common group encountered in...

 with acyl halides or alkyl halides as reactants.


The catalyst is most typically aluminium trichloride, but almost any strong Lewis acid
Lewis acid
]The term Lewis acid refers to a definition of acid published by Gilbert N. Lewis in 1923, specifically: An acid substance is one which can employ a lone pair from another molecule in completing the stable group of one of its own atoms. Thus, H+ is a Lewis acid, since it can accept a lone pair,...

 can be used. In Friedel-Crafts acylation, a full measure of aluminium trichloride must be used, as opposed to a catalytic amount.

Other reactions

  • Other reactions that follow an electrophilic aromatic substitution pattern are a group of aromatic formylation reactions including the Vilsmeier-Haack reaction
    Vilsmeier-Haack reaction
    The Vilsmeier–Haack reaction is the chemical reaction of a substituted amide with phosphorus oxychloride and an electron-rich arene to produce an aryl aldehyde or ketone . The reaction is named after Anton Vilsmeier and Albrecht Haack...

    , the Gattermann Koch reaction and the Reimer-Tiemann reaction
    Reimer-Tiemann reaction
    The Reimer-Tiemann reaction is a chemical reaction used for the ortho-formylation of phenols. The reaction was discovered by Karl Ludwig Reimer and Ferdinand Tiemann...

    .
  • Other electrophiles are aromatic diazonium salts in diazonium couplings, carbon dioxide
    Carbon dioxide
    Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...

     in the Kolbe-Schmitt reaction
    Kolbe-Schmitt reaction
    The Kolbe–Schmitt reaction/Kolbe process is a carboxylation chemical reaction that proceeds by heating sodium phenolate with carbon dioxide under pressure , then treating the product with sulfuric acid...

     and activated carbonyl
    Carbonyl
    In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....

     groups in the Pechmann condensation
    Pechmann condensation
    The Pechmann condensation is a synthesis of coumarins, starting from a phenol and a carboxylic acid or ester containing a β-carbonyl group . The condensation is performed under acidic conditions. The mechanism involves an esterification/transesterification followed by attack of the activated...

    .
  • In the multistep Lehmstedt-Tanasescu reaction
    Lehmstedt-Tanasescu reaction
    The Lehmstedt-Tanasescu reaction is a method in organic chemistry for the organic synthesis of acridone derivatives from a 2-nitrobenzaldehyde and an arene compound :...

    , 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
    Amide
    In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...


Basic reaction mechanism

In the first step of the reaction mechanism
Reaction mechanism
In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical change occurs.Although only the net chemical change is directly observable for most chemical reactions, experiments can often be designed that suggest the possible sequence of steps in...

 for this reaction, the electron-rich aromatic ring which in the simplest case is benzene
Benzene
Benzene is an organic chemical compound. It is composed of 6 carbon atoms in a ring, with 1 hydrogen atom attached to each carbon atom, with the molecular formula C6H6....

 attacks the electrophile A. This leads to the formation of a positively-charged cyclohexadienyl cation, also known as an arenium ion
Arenium ion
An arenium ion in organic chemistry is a cyclohexadienyl cation that appears as a reactive intermediate in electrophilic aromatic substitution. For historic reasons this complex is also called a Wheland intermediate or a sigma complex or σ-complex.Two hydrogen atoms bonded to one carbon lie in a...

. This carbocation
Carbocation
A carbocation is an ion with a positively-charged carbon atom. The charged carbon atom in a carbocation is a "sextet", i.e. it has only six electrons in its outer valence shell instead of the eight valence electrons that ensures maximum stability . Therefore carbocations are often reactive,...

 is unstable, owing both to the positive charge on the molecule and to the temporary loss of aromaticity
Aromaticity
In organic chemistry, Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit a stabilization stronger than would be expected by the stabilization of conjugation alone. The earliest use of the term was in an article by August...

. However, the cyclohexadienyl cation is partially stabilized by resonance
Resonance (chemistry)
In chemistry, resonance or mesomerism is a way of describing delocalized electrons within certain molecules or polyatomic ions where the bonding cannot be expressed by one single Lewis formula...

, 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 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
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...

s. Performing an electrophilic substitution on an already substituted benzene compound raises the problem of regioselectivity
Regioselectivity
In chemistry, regioselectivity is the preference of one direction of chemical bond making or breaking over all other possible directions. It can often apply to which of many possible positions a reagent will affect, such as which proton a strong base will abstract from an organic molecule, or where...

. In case of a monosubstituted benzene, there are 4 different reactive positions. For a monosubstituted benzene, the ring carbon atom bearing the substituent
Substituent
In organic chemistry and biochemistry, a substituent is an atom or group of atoms substituted in place of a hydrogen atom on the parent chain of a hydrocarbon...

 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 group
Activating group
In organic chemistry, a functional group is called an activating group if a benzene molecule to which it is attached more readily participates in electrophilic substitution reactions...

s stabilize the cationic intermediate formed during the substitution by donating electrons into the ring system, by either inductive effect
Inductive effect
In chemistry and physics, the inductive effect is an experimentally observable effect of the transmission of charge through a chain of atoms in a molecule by electrostatic induction...

 or resonance effects. Examples of activated aromatic rings are toluene
Toluene
Toluene, formerly known as toluol, is a clear, water-insoluble liquid with the typical smell of paint thinners. It is a mono-substituted benzene derivative, i.e., one in which a single hydrogen atom from the benzene molecule has been replaced by a univalent group, in this case CH3.It is an aromatic...

, aniline
Aniline
Aniline, phenylamine or aminobenzene is an organic compound with the formula C6H5NH2. Consisting of a phenyl group attached to an amino group, aniline is the prototypical aromatic amine. Being a precursor to many industrial chemicals, its main use is in the manufacture of precursors to polyurethane...

 and phenol
Phenol
Phenol, also known as carbolic acid, phenic acid, is an organic compound with the chemical formula C6H5OH. It is a white crystalline solid. The molecule consists of a phenyl , bonded to a hydroxyl group. It is produced on a large scale as a precursor to many materials and useful compounds...

.

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
Deactivating groups
In organic chemistry, a deactivating group is a functional group attached to a benzene molecule that removes electron density from the benzene ring, making electrophilic aromatic substitution reactions slower and more complex relative to benzene...

 destabilize the intermediate cation and thus decrease the reaction rate
Reaction rate
The reaction rate or speed of reaction for a reactant or product in a particular reaction is intuitively defined as how fast or slow a reaction takes place...

. 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
Nitrobenzene
Nitrobenzene is an organic compound with the chemical formula C6H5NO2. It is a water-insoluble pale yellow oil with an almond-like odor. It freezes to give greenish-yellow crystals. It is produced on a large scale as a precursor to aniline. Although occasionally used as a flavoring or perfume...

, benzaldehyde
Benzaldehyde
Benzaldehyde is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful. This colorless liquid has a characteristic pleasant almond-like odor...

 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
Nitration
Nitration is a general chemical process for the introduction of a nitro group into a chemical compound. The dominant application of nitration is for the production of nitrobenzene, the precursor to methylene diphenyl diisocyanate...

 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
Sulfuric acid
Sulfuric acid is a strong mineral acid with the molecular formula . Its historical name is oil of vitriol. Pure sulfuric acid is a highly corrosive, colorless, viscous liquid. The salts of sulfuric acid are called sulfates...

.

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
Aniline
Aniline, phenylamine or aminobenzene is an organic compound with the formula C6H5NH2. Consisting of a phenyl group attached to an amino group, aniline is the prototypical aromatic amine. Being a precursor to many industrial chemicals, its main use is in the manufacture of precursors to polyurethane...

, are strongly activating and ortho/para-directing. Such activating group
Activating group
In organic chemistry, a functional group is called an activating group if a benzene molecule to which it is attached more readily participates in electrophilic substitution reactions...

s donate those unshared electrons to the pi system.


When the electrophile attacks the ortho
Arene substitution patterns
Arene substitution patterns are part of organic chemistry IUPAC nomenclature and pinpoint the position of substituents other than hydrogen in relation to each other on an aromatic hydrocarbon.- Ortho, meta, and para substitution :...

 and para
Arene substitution patterns
Arene substitution patterns are part of organic chemistry IUPAC nomenclature and pinpoint the position of substituents other than hydrogen in relation to each other on an aromatic hydrocarbon.- Ortho, meta, and para substitution :...

 positions of aniline, the nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...

 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
Aryl
In the context of organic molecules, aryl refers to any functional group or substituent derived from an aromatic ring, be it phenyl, naphthyl, thienyl, indolyl, etc....

 substituent
Substituent
In organic chemistry and biochemistry, a substituent is an atom or group of atoms substituted in place of a hydrogen atom on the parent chain of a hydrocarbon...

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.

Halogen
Halogen
The halogens or halogen elements are a series of nonmetal elements from Group 17 IUPAC Style of the periodic table, comprising fluorine , chlorine , bromine , iodine , and astatine...

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 groups.

Directed ortho metalation
Directed ortho metalation
Directed ortho metalation is an adaptation of electrophilic aromatic substitution in which electrophiles attach themselves exclusively to the ortho- position of a direct metalation group or DMG through the intermediary of an aryllithium compound . The DMG interacts with lithium through a hetero atom...

 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) draw substantial electron density from the pi system. These groups are strongly deactivating groups
Deactivating groups
In organic chemistry, a deactivating group is a functional group attached to a benzene molecule that removes electron density from the benzene ring, making electrophilic aromatic substitution reactions slower and more complex relative to benzene...

. 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 directing.

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
Salicylic acid
Salicylic acid is a monohydroxybenzoic acid, a type of phenolic acid and a beta hydroxy acid. This colorless crystalline organic acid is widely used in organic synthesis and functions as a plant hormone. It is derived from the metabolism of salicin...

 with a mixture of nitric
Nitric acid
Nitric acid , also known as aqua fortis and spirit of nitre, is a highly corrosive and toxic strong acid.Colorless when pure, older samples tend to acquire a yellow cast due to the accumulation of oxides of nitrogen. If the solution contains more than 86% nitric acid, it is referred to as fuming...

 and sulfuric acid
Sulfuric acid
Sulfuric acid is a strong mineral acid with the molecular formula . Its historical name is oil of vitriol. Pure sulfuric acid is a highly corrosive, colorless, viscous liquid. The salts of sulfuric acid are called sulfates...

 to form picric acid
Picric acid
Picric acid is the chemical compound formally called 2,4,6-trinitrophenol . This yellow crystalline solid is one of the most acidic phenols. Like other highly nitrated compounds such as TNT, picric acid is an explosive...

. 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
Hayashi rearrangement
The Hayashi rearrangement is the chemical reaction of ortho-benzoylbenzoic acids catalyzed by sulfuric acid or phosphorus pentoxide.This reaction proceeds through electrophilic acylium ion attack with a spiro intermediate....

.

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

Five membered heterocyclic compounds

Furan
Furan
Furan is a heterocyclic organic compound, consisting of a five-membered aromatic ring with four carbon atoms and one oxygen. The class of compounds containing such rings are also referred to as furans....

, Thiophene
Thiophene
Thiophene is a heterocyclic compound with the formula C4H4S. Consisting of a flat five-membered ring, it is aromatic as indicated by its extensive substitution reactions. Related to thiophene are benzothiophene and dibenzothiophene, containing the thiophene ring fused with one and two benzene...

, Pyrrole
Pyrrole
Pyrrole is a heterocyclic aromatic organic compound, a five-membered ring with the formula C4H4NH. It is a colourless volatile liquid that darkens readily upon exposure to air. Substituted derivatives are also called pyrroles, e.g., N-methylpyrrole, C4H4NCH3...

 and their derivatives are all highly activated compared to benzene. These compounds all contain an atom with an unshared pair of electrons (oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...

, sulphur, or nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...

) as a member of the aromatic ring, which substantially increases the stability of the cationic intermediate. Examples of electrophilic substitutions to pyrrole
Pyrrole
Pyrrole is a heterocyclic aromatic organic compound, a five-membered ring with the formula C4H4NH. It is a colourless volatile liquid that darkens readily upon exposure to air. Substituted derivatives are also called pyrroles, e.g., N-methylpyrrole, C4H4NCH3...

 are the Pictet-Spengler reaction
Pictet-Spengler reaction
The Pictet–Spengler reaction is a chemical reaction in which a β-arylethylamine such as tryptamine undergoes ringclosure after condensation with an aldehyde or ketone. Usually an acidic catalyst is employed and the reaction mixture heated, but some reactive compounds give good yields even at...

 and the Bischler-Napieralski reaction
Bischler-Napieralski reaction
The Bischler–Napieralski reaction is an intramolecular electrophilic aromatic substitution reaction that allows for the cyclization of β-arylethylamides or β-arylethylcarbamates. It was first discovered in 1893 by August Bischler and Bernard Napieralski, in affiliation with Basle Chemical Works and...

.

Asymmetric electrophilic aromatic substitution

Electrophilic aromatic substitutions with prochiral
Prochiral
In stereochemistry, prochiral molecules are those that can be converted from achiral to chiral in a single step.If two identical substituents are attached to a sp3-hybridized atom, the descriptors pro-R and pro-S are used to distinguish between the two...

 carbon electrophiles have been adapted for asymmetric synthesis by switching to chiral
Chirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....

 Lewis acid
Lewis acid
]The term Lewis acid refers to a definition of acid published by Gilbert N. Lewis in 1923, specifically: An acid substance is one which can employ a lone pair from another molecule in completing the stable group of one of its own atoms. Thus, H+ is a Lewis acid, since it can accept a lone pair,...

 catalysts especially in Friedel-Crafts type reactions
Friedel-Crafts reaction
The Friedel–Crafts reactions are a set of reactions developed by Charles Friedel and James Crafts in 1877. There are two main types of Friedel–Crafts reactions: alkylation reactions and acylation reactions. This reaction type is a form of electrophilic aromatic substitution...

. An early example concerns the addition of chloral
Chloral
Chloral, also known as trichloroacetaldehyde, is the organic compound with the formula Cl3CCHO. This aldehyde is a colourless oily liquid that is soluble in a wide range of solvents...

 to phenols
Phenols
In organic chemistry, phenols, sometimes called phenolics, are a class of chemical compounds consisting of a hydroxyl group bonded directly to an aromatic hydrocarbon group...

 catalyzed by aluminium chloride
Aluminium chloride
Aluminium chloride is the main compound of aluminium and chlorine. It is white, but samples are often contaminated with iron trichloride, giving it a yellow colour. The solid has a low melting and boiling point. It is mainly produced and consumed in the production of aluminium metal, but large...

 modified with (-)-menthol
Menthol
Menthol is an organic compound made synthetically or obtained from peppermint or other mint oils. It is a waxy, crystalline substance, clear or white in color, which is solid at room temperature and melts slightly above. The main form of menthol occurring in nature is -menthol, which is assigned...

. A glyoxylate compound has been added to N,N-dimethylaniline
Dimethylaniline
N,N-Dimethylaniline is an organic chemical compound, a substituted derivative of aniline. It consists of a tertiary amine, featuring dimethylamino group attached to a phenyl group. This oily liquid is colourless when pure, but commercial samples are often yellow...

 with a chiral bisoxazoline ligand
Bisoxazoline ligand
In chemistry, bisoxazoline ligands are chiral ligands based on a bis oxazoline skeleton and used in combination with a metal compound in asymmetric synthesis as a chiral catalyst . Three frequently encountered such ligands are PyBOX, tBuBOX and PhBOX...

 - copper(II) triflate
Copper(II) triflate
Copper triflate is the copper salt of trifluoromethanesulfonic acid which has a chemical formula of Cu2. This substance is a powerful Lewis acid which is used as catalyst in several organic reactions....

 catalyst system also in a Friedel-Crafts hydroxyalkylation :


In another alkylation N-methylpryrrole
Pyrrole
Pyrrole is a heterocyclic aromatic organic compound, a five-membered ring with the formula C4H4NH. It is a colourless volatile liquid that darkens readily upon exposure to air. Substituted derivatives are also called pyrroles, e.g., N-methylpyrrole, C4H4NCH3...

 reacts with crotonaldehyde
Crotonaldehyde
Crotonaldehyde is a chemical compound with the formula CH3CH=CHCHO. The compound is usually sold as a mixture of the E- and Z-isomers, which differ with respect to the relative position of the methyl and formyl groups. The E-isomer is more common...

 catalyzed by trifluoroacetic acid
Trifluoroacetic acid
Trifluoroacetic acid is the simplest stable perfluorinated carboxylic acid chemical compound, with the formula CF3CO2H. It is a strong carboxylic acid due to the influence of the electronegative trifluoromethyl group. TFA is almost 100,000-fold more acidic than acetic acid...

 modified with a chiral imidazolidinone
Imidazole
Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...

 :


Indole
Indole
Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Indole is a popular component of fragrances and the precursor to many pharmaceuticals. Compounds that contain an...

 reacts with an enamide catalyzed by a chiral BINOL derived phosphoric acid
Phosphoric acid
Phosphoric acid, also known as orthophosphoric acid or phosphoric acid, is a mineral acid having the chemical formula H3PO4. Orthophosphoric acid molecules can combine with themselves to form a variety of compounds which are also referred to as phosphoric acids, but in a more general way...

 :


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
Enantiomeric excess
The enantiomeric excess of a substance is a measure of how pure it is. In this case, the impurity is the undesired enantiomer .-Definition:...

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