# Organic Chemistry/Aromatic reactions

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\<\< Aromatics \| Aromatic
reactions \| Ketones and
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The lack of reactivity of arenes is notable when compared to the
reactivities of typical compounds containing multiple conjugated double
bonds. For example, 1,3,5-hexatriene is much more reactive than hexane,
hexene, or any hexadiene. Benzene is much less reactive than any of
these. Any of the alkenes will be readily converted to alcohols in the
presence of a dilute aqueous solution of H~2~SO~4~, but benzene is
inert. Similarly, alkenes react readily with halogens and hydrogen
halides *by addition* to give alkyl halides, whereas halogens react with
benzene *by substitution* and only in the presence of a catalyst.
KMnO~4~ or chromic acid solutions (typically CrO~3~ or K~2~Cr~2~O~7~)
cleave the double bonds of alkenes, giving ketones or carboxylic acids,
but do not react at all with benzene. Because of the stability of
aromatic compounds, however, reactions involving these have extremely
high activation energies, for passage to the transition state
necessarily requires disruption of the aromatic system, resulting in a
temporary loss of aromatic stabilization energy. Instead of reacting by
addition and elimination, as nonaromatic compounds often do, benzene and
its derivatives usually react by electrophilic aromatic substitution.

# Redox

## Birch reduction

The **Birch reduction**[^1] is the reduction of aromatic compounds by
sodium in liquid ammonia. It is attributed to the chemist Arthur
Birch. The reaction product is a
1,4-cyclohexadiene. The metal can also be lithium or potassium and the
hydrogen atoms are supplied by an alcohol such as ethanol or
tert-butanol.

!Birch reduction of aromatic
rings

The first step of a Birch reduction is a one-electron reduction of the
aromatic ring to a radical anion. Sodium is oxidized to the sodium ion
Na^+^. This intermediate is able to dimerize to the dianion. In the
presence of an alcohol the second intermediate is a free radical which
takes up another electron to form the carbanion. This carbanion
abstracts a proton from the alcohol to form the cyclohexadiene.
center\|Birch reduction reaction
mechanism

In the presence of an alkyl halide, the carbanion can also engage in
nucleophilic substitution with carbon-carbon bond formation. In
substituted aromatics an electron withdrawing substituent such as a
carboxylic acid stabilizes a carbanion and the least-substituted alkene
is generated. With an electron donating substituent, the opposite effect
occurs. The non-conjugated 1,4-addition product is preferred over the
conjugated 1,3-diene which is explicable by the principle of least
motion. Experimental alkali
metal alternatives that are safer to handle, such as the M-SG reducing
agent, also exist.

## Oxidation of Benzene in the Human Body

Because benzene is nonpolar, it cannot be passed in urine, and will
remain in the body until oxidized. Benzene itself is not dangerous to
health, but in order to be passed, it is oxidized by cytochrome P-450 in
the liver. This produces benzene oxide, a highly teratogenic and
carcinogenic compound. Benzene has been replaced by toluene as an
industrial solvent, because toluene can be oxidized to benzoic acid,
which is mostly harmless to health, and is quickly passed. The
decomposition of benzoic acid into benzene and carbon dioxide in soda
pop has become an issue recently.

# Nucleophilic Aromatic Substitution

A nucleophilic substitution is a substitution reaction in organic
chemistry in which the nucleophile displaces a good leaving group, such
as a halide on an aromatic ring. In order to understand this type of
reaction, it is important to recognize which chemical groups are good
leaving groups and which are not.

## Leaving Groups

A leaving group can probably most simply be described as an atom or
molecule that detaches from an organic molecule. The ability for a
functional group to leave is called *lability*. Leaving groups affect
the intrinsic reactivity of the molecule as a whole, but only until,
quite naturally, they actually leave.

The lower the p*K*~a~ of the conjugate acid for a given leaving group,
the better that leaving group is at actually leaving. This is because
such groups can easily stabilize any developing negative charge and
without stabilization, a leaving group will actually become a
nucleophile causing the reaction to cycle pointlessly between attached
and detached forms. (This explains why a strong base is nearly always a
poor leaving group.)

In room temperature water, the sequence of lability is:

-   *Less lability*
-   amine/amide (NH~2~^-^)
-   alkoxy/alkoxide (RO^-^)
-   hydroxyl/hydroxide (HO^-^)
-   carboxylate (RCOO^-^)
-   fluoro/fluoride (F^-^)
-   water (H~2~O)
-   chloro/chloride (Cl^-^)
-   bromo/bromide (Br^-^)
-   iodo/iodide (I^-^)
-   azide (N~3~^-^)
-   thiocyanate (SCN^-^)
-   nitro/nitrite (NO~2~)
-   cyano/cyanide (CN^-^)
-   *Greater Lability*

## Rate of Reaction

The better a leaving group, the faster a nucleophilic reaction will
occur. This is demonstrated by comparisons of the kinetics between
halogenalkanes, where the bromides dissociate more quickly than the
chlorides, but the iodides dissociate more rapidly than either of the
other two. This is because the bond between the halogen and its nearest
carbon must be broken at some point for a nucleophilic substitution to
take place. A bond between iodine and carbon is far more polarizable
than a bond between carbon and chlorine, for example, due to iodine\'s
relatively large size and relatively large number of ionizable
electrons. The fact that water is a far better leaving group than
hydroxide also has the important consequence that the rate of a reaction
in which hydroxide leaves is increased dramatically by the presence of
an acid, for hydroxide is then protonated to water, a much weaker
nucleophile.

## Types of Reactions

There are three nucleophilic substitution mechanisms commonly
encountered with aromatic systems, the SNAr (addition-elimination)
mechanism, the benzyne mechanism and the free radical SRN1 mechanism.
The most important of these is the SNAr mechanism, where electron
withdrawing groups activate the ring towards nucleophilic attack, for
example if there are nitro functional groups positioned ortho or para to
the halide leaving group. It is not generally necessary to discuss these
types in detail within the context of an introductory organic chemistry
course.

# Electrophilic Aromatic Substitution

**Electrophiles** are particles with a deficiency of electrons.
Therefore they are likely to react with substances that have excess
electrons. Aromatic compounds have increased electron density in the
form of delocalized π-orbitals.

## Step 1: Formation of a π-complex

At first, the electrophile interacts with the delocalized orbitals of
the aromatic ring and a π-complex is formed.

![](Electrophilic_substitution_pi_complex.png "Electrophilic_substitution_pi_complex.png")

No chemical bonds are formed at this stage. Evidence of the formation of
a π-complex as an intermediate state has been found for some reactions,
but not for all, since the chemical interaction in π-complexes is very
weak.

## Step 2: Formation of a σ-complex

After the π-complex is formed, in the presence of an electron acceptor
another complex is formed - the σ-complex. It is a cationic species, an
intermediate that lacks aromatic properties, but its four π-electrons
are delocalized across the ring, which stabilizes the cation somewhat,
sometimes allowing its isolation. An example would be the salt mesityl
fluoroborate, which is stable at low temperatures, and is prepared by
the reaction of mesitylene (1,3,5-trimethylbenzene) with fluoroboric
acid (BF~3~/HF); the cation of this salt is protonated mesitylene.
σ-complexes are also known as *Wheland intermediates*.

## Step 3: Formation of a Substituted product

At the next stage the σ-complex decomposes, freeing a hydrogen cation
and forming the product of substitution.

![](Electrophilic_substitutiom_sigma_complex.png "Electrophilic_substitutiom_sigma_complex.png")

### Electrophilic aromatic halogenation

!Electrophilic aromatic substitution of
benzene{width="450"}
Another important reaction of benzene is the electrophilic substitution
of halides, a specific type of electrophilic aromatic substitution.
These reactions are very useful for adding substituents to an aromatic
system. The rates of the reactions increase with the electrophilicity of
the halogen: hence, fluorination in this manner is too rapid and
exothermic to be practical, whereas iodine requires the most vigorous
conditions. Chlorination and bromination are the most often practiced in
the lab of the four possible halogenations. Halobenzenes are used for
pesticides, as well as the precursors to other products. Many COX-2
inhibitors contain halobenzene subunits.

Some highly activated aromatic compounds, such as phenol and aniline,
are reactive enough to undergo halogenation without a catalyst, but for
typical benzene derivatives (and benzene itself), the reactions are
extremely slow at room temperature in the absence of a catalyst.
Usually, Lewis acids are used as catalysts, which work by helping to
polarize the halogen-halogen bond, thus decreasing the electron density
around one halogen atom, making it more electrophilic. The most common
catalysts used are either Fe or Al, or their respective chlorides and
bromides (+3 oxidation state). Iron(III) bromide and iron(III) chloride
lose their catalytic activity if they are hydrolyzed by any moisture
present, including atmospheric water vapor. Therefore, they are
generated *in situ* by adding iron fillings to bromine or chlorine.
Iodination is carried out under different conditions: periodic acid is
often used as a catalyst. Under these conditions, the I^+^ ion is
formed, which is sufficiently electrophilic to attack the ring.
Iodination can also be accomplished using a diazonium reaction.
Fluorination is most often done using this technique, as the use of
fluorine gas is inconvenient and often fragments organic compounds.

Halogenation of aromatic compounds differs from the additions to alkenes
or the free-radical halogenations of alkanes, which do not require Lewis
acid catalysts. The formation of the arenium ion results in the
temporary loss of aromaticity, the overall result being that the
reaction\'s activation energy is higher than those of halogenations of
aliphatic compounds.

Halogenation of phenols is faster in polar solvents due to the
dissociation of phenol, because the phenoxide (-O^-^) group is more
strongly activating than hydroxyl itself.

### Electrophilic 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.

The electrophile of such a reaction is sulfur trioxide (SO~3~), which
can be released from oleum (also known as fuming sulfuric acid),
essentially sulfuric acid in which gaseous sulfur trioxide has been
dissolved.

In contrast to aromatic nitration and other electrophilic aromatic
substitutions, aromatic sulfonation is reversible. Sulfonation takes
place in strongly acidic conditions, and desulfonation can occur on
heating with a trace of acid. This also means that thermodynamic, rather
than kinetic, control can be achieved at high temperatures. Hence,
directive effects are not expected to play a key role in determining the
proportions of isomeric products of high-temperature sulfonation.

Aromatic sulfonic acids can be intermediates in the preparation of dyes
and many pharmaceuticals. Sulfonation of aniline produces
p-aminobenzenesulfonic acid or sulfanilic acid, which is a zwitterionic
compound with an unusually high melting point. The amide of this
compound and related compounds form a large group of sulfa drugs (a type
of antibiotic).

Overall reaction: ArH + SO~3~ → ArSO~3~H

### Electrophilic aromatic nitration

Nitration occurs with aromatic organic compounds via an electrophilic
substitution mechanism involving the attack of the electron-rich benzene
ring by the nitronium (nitryl) ion. Benzene is commonly nitrated by
refluxing with a mixture of concentrated sulfuric acid and concentrated
nitric acid at 50°C. The sulfuric acid is regenerated and hence acts as
a catalyst.

Selectivity is always a challenge in nitrations. Fluorenone nitration is
selective and yields a tri-nitro compound or tetra-nitro compound by
tweaking reaction conditions just slightly. Another example of
trinitration can be found in the synthesis of phloroglucinol. Other
nitration reagents include nitronium tetrafluoroborate which is a true
nitronium salt. This compound can be prepared from hydrogen fluoride,
nitric acid and boron trifluoride. Aromatic nitro compounds are
important intermediates for anilines; the latter may be readily prepared
by action of a reducing agent.

Overall reaction: ArH + HNO~3~ → ArNO~2~ + H~2~O

### Friedel-Crafts alkylation

!Friedel-Crafts alkylation of benzene with methyl
chloride{width="400"}

The Friedel-Crafts reactions, discovered by French alkaloid chemist
Charles Friedel and his American partner, James Crafts, in 1877, is
either the alkylation or acylation of aromatic compounds catalyzed by a
Lewis acid. They are very useful in the lab for formation of
carbon-carbon bonds between an aromatic nucleus and a side chain.

#### Source of electrophile

Friedel-Crafts alkylation is an example of electrophilic substitution in
aromatic compounds. The electrophile is formed in the reaction of an
alkyl halide with a Lewis acid. The Lewis acid polarizes the alkyl
halide molecule, causing the hydrocarbon part of it to bear a positive
charge and thus become more electrophilic.

CH~3~---Cl + AlCl~3~ → CH~3~^+^ + AlCl~4~^−^

or

CH~3~Cl + AlCl~3~ → CH~3~^δ+^Cl^+^Al^−^Cl~3~

(The carbon atom has a slight excess of positive charge, as the
electronegative chlorine atom draws electron density towards itself. The
chlorine atom has a positive charge, as it has formed a sub-ordinate
bond with the aluminium atom. In effect, the Cl atom has lost an
electron, while the Al atom has gained an electron. Therefore, the Al
atom has a negative charge.)

#### Mechanism of alkylation

The polarized, electrophilic molecule then seeks to saturate its
electron deficiency and forms a π-complex with the aromatic compound
that is rich in π-electrons. Formation a π-complex does not lead to loss
of aromaticity. The aromaticity is lost however in the σ-complex that is
the next stage of reaction. The positive charge in the σ-complex is
evenly distributed across the benzene ring.

C~6~H~6~ + CH~3~^+^ → C~6~H~6~^+^Br → C~6~H~5~Br + H^+^

The σ-complex C~6~H~6~^+^Br can be separated (it is stable at low
temperatures), while the π-complex can not.

#### Restrictions

-   Deactivating functional groups, such as nitro (-NO~2~), usually
    prevent the reaction from occurring at any appreciable rate, so it
    is possible to use solvents such as nitrobenzene for Friedel-Crafts
    alkylation.

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-   Primary and secondary carbocations are much less stable than
    tertiary cations, so rearrangement typically occurs when one
    attempts to introduce primary and secondary alkyl groups onto the
    ring. Hence, Friedel-Crafts alkylation using n-butyl chloride
    generates the n-butylium cation, which rearranges to the t-butyl
    cation, which is far more stable, and the product is exclusively the
    t-butyl derivative. This may, in some cases, be circumvented through
    use of a weaker Lewis acid.

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-   The Friedel-Crafts reaction can not be used to alkylate compounds
    which are sensitive to acids, including many heterocycles.

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-   Another factor that restricts the use of Friedel-Crafts alkylation
    is polyalkylation. Since alkyl groups have an activating influence,
    substituted aromatic compounds alkylate more easily than the
    original compounds, so that the attempted methylation of benzene to
    give toluene often gives significant amounts of xylene and
    mesitylene. The usual workaround is to acylate first (see the
    following sections) and then reduce the carbonyl group to an alkyl
    group.

### Friedel-Crafts acylation

!Friedel-Crafts acylation of benzene by acetyl
chloride{width="300"}

Friedel-Crafts acylation, like Friedel-Crafts alkylation, is a classic
example of electrophilic substitution.

#### Source of electrophile

Reacting with Lewis acids, anhydrides and chloranhydrides of acids
become strongly polarized and often form acylium cations.

RCOCl + AlCl~3~ → RC^+^O + AlCl~4~^-^

#### Mechanism of acylation

The mechanism of acylation is very similar to that of alkylation.

C~6~H~6~ + RC^+^O → C~6~H~6~---CO---R + H^+^

The ketone that is formed then forms a complex with aluminum chloride,
reducing its catalytic activity.

C~6~H~6~---CO---R + AlCl~3~ → C~6~H~6~---C^+^(R)---O---Al^−^Cl~3~

Therefore, a much greater amount of catalyst is required for acylation
than for alkylation.

#### Restrictions

-   Although no isomerisation of cations happens, due to the reasonance
    stabilization provided by the acylium ion, certain cations may lose
    CO and alkylation will occur instead of acylation. For example, an
    attempt to add pivalyl (neopentanoyl) to an aromatic ring will
    result in loss of CO from the cation, which then results in the
    t-butyl derivative being formed.
-   Acidophobic aromatic compounds, such as many heterocycles can\'t
    exist in the presence of both Lewis acids and anhydrides.
-   Formyl chloride is unstable and cannot be used to introduce the
    formyl group onto a ring through Friedel-Crafts acylation. Instead,
    the Gattermann-Koch reaction is often used.

#### Applications

Friedel-Crafts acylation is used, for example, in the synthesis of
anthraquinone from benzene and phtalic anhydride.

In laboratory synthesis Friedel-Crafts acylation is often used instead
of alkylation in cases where alkylation is difficult or impossible, such
as synthesis of monosubstituted alkylbenzenes.

# External links

-   reduction of o-anisic acid to
    2-heptyl-2-hexenone in Organic
    Syntheses
    Article
-   reduction of naphthalene to
    1,4,5,8-Tetrahydronaphthalene (isotetralin) in Organic
    Syntheses
    Article.
-   reduction of o-xylene to
    1,2-Dimethyl-1,4-cyclohexadiene in Organic
    Syntheses
    Article
-   reduction of benzoic acid to
    2,5-Cyclohexadiene-1-carboxylic acid in Organic
    Syntheses
    Article

# References

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\<\< Aromatics \| Aromatic
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[^1]: \* A. J. Birch, J. Chem. Soc. **1944**, 430.
