Reactions of Aromatic Compounds

Simple alkenes tend to undergo addition reactions:

HBr Br
2
Br
Br Br
C
3
H
6
C
3
H
6
Br
2
C
3
H
7
Br


The elements of the reagent (HBr or Br
2
) are simply added to the starting material. This is
called, unsurprisingly, and addition reaction.
Aromatic compounds do not react in this manner. A look at a simple aromatic
bromination:
Br
2
/ FeBr
3
Br
C
6
H
6
C
6
H
5
Br

What we have done in this case is substitute a bromine for a hydrogen. Hence the term
aromatic substitution. Because the benzene ring is quite electron-rich, it almost always
behaves as the nucleophile in a reaction - which means that the substitution on benzene occurs by
the addition of an electrophile -> electrophilic aromatic substitution.

There is basically one simple mechanism for all electrophilic aromatic substitutions:
E
+
H
E
H
E
H
E
B
-
E

The benzene acts as a nucleophile, attacking the electrophile with a pair of its !-electrons.
This initial step destroys the aromaticity of the molecule! The resulting positive charge is
delocalized over the ortho and para positions. The conjugate base of the initial electrophile then
assists in removing the now-extraneous proton, and restores aromaticity. Because all
electrophilic aromatic substitutions proceed in this way, the only thing that matters is the
preparation of a hot electrophile.
Why a hot electrophile? As you can see, the first step of the reaction involves
destroying aromaticity. In order to do this, there must be a significant energetic driving force.
This driving force comes in the form of a very reactive (unhappy) electrophile.
How are such electrophiles generated?
Halogenation
As you can imagine, halogens bearing a positive charge are particularly reactive. I will
focus on preparing halogen electrophiles from Br, Cl and I.
Bromine: Allowing bromine to react with iron metal first generates FeBr
3
, which then
interacts with the remaining Br
2
to form a highly polarized system:
Fe
Br
2
FeBr
3
Br
3
Fe Br Br
!
-
!
+

It is this highly polarized bromine that becomes a source of Br
+
. The reaction proceeds
by the mechanism shown above to give brominated benzene:
Br
2
FeBr
3
Br

Chlorine: The same chemistry shown for bromine also works with chlorine to generate
Cl
+
. A mixture of benzene, chlorine and iron(III)chloride yields the chlorobenzene:
Cl
2
FeCl
3
Cl

Iodine: It is a little more difficult to make iodine sufficiently electrophilic. For relatively
activated compounds, where a mild source of I
+
is required, copper salts are often used as a
catalyst:
I
2
CuCl
2
I
I
2
+ 2 Cu
++
--> 2 "I
+
" + 2 CuI

Reaction then proceeds by the standard mechanism, with I
+
as the electrophile, to give iodinated
benzenes.
For more de-activated systems, or when more than one iodine needs to be added to the
ring, a harsher reagent exists:
Br Br
Br
H
2
SO
4
/ I
2
H
5
IO
6
Br Br
Br
I I
I


Why?
You should always ask this question. What good are aromatic halides? The halogens are
excellent synthetic handles they can be easily converted into other functional groups. For
example, bromobenzenes can be turned into Grignard reagents, and the reacted with aldehydes,
ketones, etc....
Br
Mg
BrMg
O
HO
OMe
O
HO
CO
2
COOH


NITRATION
We can also make a highly electrophilic form of NO
2
:
N
O
O
O
H
HSO
4
H
N
O
O
O
H
H
O
N
O

Which can then react with aromatic compounds via the standard mechanism to give nitrated
aromatics...
O
N
O
N
O
O
etc.

Why? There are a couple of good reasons to nitrate things. The first is in the manufacture of
explosives highly nitrated organic molecules are frequently used as explosives
(trinitrotoluene(TNT), nitroglycerine, etc.). The second reason is that nitro-groups are generally
easy to reduce to amines. And since it is nearly impossible to make an amine electrophilic (in
order to add it to an aromatic ring under electrophilic aromatic substitution conditions), aromatic
nitro compounds are about the only precursors to aromatic amines:
NO
2
1) SnCl
2
/ H
+
2) HO
-
NH
2


Sulfonation
Just as with nitration, it is easy to make a solution of highly electrophilic SO
3
. This
solution can be used to sulfonate aromatic compounds:
O
S
OH
S
HO
O
O
O
H
SO
3
H
lose proton

Why? First of all, the reaction is REVERSIBLE!!! Cook it up in hot AQUEOUS acid,
and the SO
3
group falls right off again. Second, aromatic sulfonic acids were used as the first
antibiotics - the so-called sulfa drugs (sulfanilamide, etc.) They can also be used in making
detergents (oh, what fun.)

Friedel-Crafts Reactions:
This reaction comes in two flavors - alkylation and acylation. Alkylation first:
The basic premise of this reaction is the electrophilic addition of alkyl groups to an
aromatic ring. The general scheme:
R-Cl + AlCl
3
R
+
+ AlCl
4
-
R
+
+
R
(R = alkyl)

A simple example:
Cl
AlCl
3

There are a number of drawbacks to this reaction:
1) Does not work at all on aromatic rings with de-activating groups (nitro, any carbonyl,
cyano) attached.
2) Because alkyl groups are activating, over-alkylation is a significant problem.
3) Because a carbocationic intermediate is involved, rearrangements tend to take place.
For example:
Cl
H H
Major product
Cl
AlCl
3
AlCl
3
A
MESS!


However, ol Friedel & Crafts came up with another reaction without so many
drawbacks. The Friedel-Crafts acylation generally proceeds without complication:
Cl R
O
AlCl
3
R
O
O R
R
O
R
O

For example:
Cl
O
AlCl
3
O

Note the only significant restriction is that we still cant have any de-activating groups on
the ring. Over-acylation cannot be a problem because an acyl group is de-activating, only one
can add! There is also no problem with rearrangements. A very efficient!

Substituent Effects
Most of what Ive talked about so-far has involved the addition of a compound to an
unsubstituted benzene ring. What about additions to a substituted ring? I will summarize:

Activating/de-activating groups
Because the benzene rings electrons are acting as the nucleophile in all of the above
reactions, rings substituted with strong electron-donating groups (particularly !-electron
donating) are considered activated - they will often even react without a catalyst! Some
examples of activating groups are:

OH, OR, NH
2
, NR
2
, Alkyl

The oxygen and nitrogen-based activating groups increase reactivity by a resonance effect:
A
A A A

(A = OR, OH, NH
2
, NR
2
)
As you can see, the very nature of the activation requires ortho-para direction!
Alkyl groups work somewhat differently. They are not as strong at activating the ring,
and their main function is stabilizing the positive charge formed after the attack on the
electrophile:
R
E
+
R
E H
R
E H
Stable tertiary carbocation!

(R = alkyl)
Note well: All activating groups direct ortho-para!

The Halogens:
The halogens are in a class by themselves, and behave in an unusual manner. They are
VERY electron withdrawing, and thus DE-ACTIVATE the ring towards electrophilic
substitution. However, their multiple lone-pairs are able to stabilize the cation formed after
electrophilic addition, and thus direct ortho-para:

Br
E
+
E H
E H
Br Br


Meta-Directing De-activators.
Strongly electron-withdrawing groups de-activate the ring towards electrophilic
substitution. Examples of such groups are:

Ester (COOR), Acid (COOH), Aldehyde (CHO), Nitro (NO
2
), Ketone (or acyl, COR),
Cyano (CN) Acid Halide (COCl)

However, with a strong enough electrophile, the rings often will react. However, in order
to avoid putting the charge that develops (after attacking an electrophile) on the carbon attached
to the electron-withdrawing group, the incoming electrophile must attach to the meta carbons
(see below). Note that the charge cannot be delocalized onto the carbon containing the acyl
group (also note - the charge delocalizes over all of the ortho and para positions!)

O
E
+
O
E
H
O
E
H
O
E
H

Other considerations:

Sterics, Sterics, Sterics. This is particularly a problem with bulky ortho-para directors -
the ortho positions are blocked, forcing addition to the para positions:
Br
2
/ Fe
Br
NO ORTHO!
HNO
3
H
2
SO
4
NO
2


Multi-functional compounds:
What if the ring has several substituents? Your text has a rather detailed description of
what to do, so here Ill just supplement that data.
1) If the effects of two substituents point to reactivity at one particular carbon, youre in
luck! Thats where the electrophile will go (providing the sterics are not horrible).

2) The strongest directing group almost always prevails (e.g. OH over alkyl, NR
2
over
Br)

3) The order of precedence is
a) Strong o,p directors (OR, NR
2
)
b) Alkyl groups and halogen
c) All meta-directors.

4) And of course, keep a close eye on the steric environment.

Nucleophilic Aromatic Substitution
Your text has a good description of this phenomenon (Sec. 16.8). This sort of reaction is
not very common, but it would be a good idea to be familiar with the mechanism.

Benzyne
Benzyne was discovered when some crazed scientists mixed chlorobenzene and sodium
hydroxide at high temperature and pressure. The resulting phenol was found to have arisen from
an elimination/re-addition reaction:
H
Cl
HO
-
H
2
O
OH

Because benzyne is such a useful intermediate, a method has been discovered which allows it to
be prepared by much milder means. It starts with anthranilic acid, diazotizes the amine, which
then decomposes to benzyne, carbon dioxide and nitrogen. The benzyne can then be used in
many ways:

NH
2
O
OH
N
O
O
N
H
HNO
2
H
2
SO
4
("diazotization")
B
-
OR
mild base
ROH
Diels-Alder
Slow
Decomposition
Biphenylene


Reactions on the Aromatic Side Chain:
Alkyl groups attached to a benzene ring are surprisingly reactive. The hydrogens on a
carbon atom attached to the benzene ring are called benzilic. Notice a similarity to allylic
systems?
H H
Benzilic Hydrogens
H
H
Allylic hydrogens

Benzilic hydrogens show a reactivity similar to allylic hydrogens: They can be
brominated with NBS, for example:
H
N
O
O
Br
(NBS)
(PhCO)
2
O
CCl
4
Br


Aromatic compounds with benzilic hydrogens are also susceptible to oxidative
degradation: Potassium permanganate (KMnO
4
) decomposes these to the benzoic acid (caution -
you loose the WHOLE side-chain on this one!):

CH
3
KMnO
4
COOH
HO
KMnO
4
COOH
(!)
HO
KMnO
4
H
O
OH

Note - if there are NO benzilic hydrogens (last example), the benzilic position is not oxidized (in
this case, only the alcohol on the side chain gets oxidized.

Hydrogenation:
With a sufficiently active catalyst, it is possible to hydrogenate the aromatic system to a
completely saturated system. Because aromatic chemistry is so rich & diverse, this is one
method to prepare highly substituted cyclohexanes:

COOH
COOH HOOC
Rh / C, H
2
EtOH
COOH
COOH HOOC
COOH
COOH
COOH
Kemp's Triacid
(molecular recognition)


It is also extremely easy to hydrogenate a side-chain. As a simple example, take ethyl
cinnamate:
O
OEt
H
2
, Pd / C
Ethyl Acetate
100%
O
OEt


Along with hydrogenation, we can also do a different kind of reduction - a de-
oxygenation! This reaction ONLY works on Aryl Ketones (R " H), and is a PERFECT way to
turn a Friedel-Crafts Acylation into an Alkylation:
O
H
2
, Pd
R
R ! H
R
R Cl
O
AlCl
3


Aromatic amines

Preparation
There is basically one method commonly used to prepare aromatic amines, and you have
already seen it. The reduction of aromatic nitro compounds leads to the aromatic amine under
quite mild conditions. While there are a number of methods that can be used, the one I would
remember is SnCl
2
/ HCl followed by NaOH in water:
Cl
HNO
3
H
2
SO
4
Cl
NO
2
1) SnCl
2
/ HCl
2) NaOH / H
2
O
Cl
NH
2


So, an amino group is powerfully activating can this cause problems? Of course. It is
frequently necessary to tone down the reactivity of an aromatic amine, in order to get only
monosubstitution, or for Friedel-Crafts reactions to work at all(!). The absolute best way to do
this is to turn the amine into an amide (usually by allowing it to react with acetic anhydride /
pyridine). The lone pair on nitrogen becomes a bit more strongly delocalized out the amide end,
thus leaving the ring a bit less activated. After the reaction is finished, the amide can be cleaved
to give back the amine with NaOH / water (note: an amide is a bulky group, therefore additions
usually go para first):
NH
2 Cl
AlCl
3
No reaction (actually, a foul mess)
NH
2
O
O
O
Pyridine
HN
O
Cl
AlCl
3
HN
O
NaOH
H
2
O
NH
2

The next cool reaction you can do with aromatic amines it the Sandmeyer. This reaction
is probably the neatest thing about aromatic compounds in general. The Sandmeyer proceeds in
two stages. First, reaction with sodium nitrite to give the diazo compound. Basically, youre
now looking at a benzene ring with nitrogen gas stuck onto it. Who could ask for a better
leaving group? Next, you add your favorite nucleophile as a copper salt (for example, if you
wanted to add bromide, youd dump in some CuBr. If you wanted to add cyanide, dump in
CuCN, etc). Warm that puppy up for a few minutes, and voila! Instant substitution! First, a
simpler example:

NH
2
NaNO
2
aq. HCl
N
N
CuBr
Br

There are a couple of fairly cool modifications that you can do here. First, if you add
hypophosphorous acid (H
3
PO
2
) to a diazonium salt, the aromatic ring just gets protonated.
This is usually the best way to make 1,3,5-trihalobenzenes (remember - halogens are o,p-
directing!):
NH
2
I
2
NH
2
I I
I
NaNO
2
aq. HCl
N
I I
I
N
H
3
PO
2
I I
I

This is one of the best (and most common) ways to abuse an aromatic amine - you just
use it for its activating and directing effects, then you throw it away.
Another modification can be used to make phenols: If you just add water to the
diazonium salt, you add an OH group to the ring:
N
N
H
2
O
OH


Cyanide is also pretty easy to add:
NH
2
COOH
I
I
HOOC
I
NaNO
2
aq. HCl
N
COOH
I
I
HOOC
I
N
CuCN
NaCN
C
COOH
I
I
HOOC
I
N
H
2
SO
4



Phenols and Quinones

Aromatic alcohols are not quite as reactive as aromatic amines: The lone pair is not
nearly so hyperactive. However, aromatic alcohols (called phenols) are very easy to deprotonate
(no surprise here - the resulting negative charge is delocalized over the ring!), leading to an anion
that is mildly basic and very nucleophilic.
The acidity of the phenolic proton is also highly dependent on the other substituents on
the aromatic ring. Electron withdrawing groups stabilize the anion, and thus make the phenol
more acidic (for example, trinitrophenol is VERY acidic). Electron-donating groups have the
opposite effect.
Preparation:

The best way to make phenols is to use the cool reaction you learned with aromatic
amines, the Sandmeyer. This reaction is usually done last in a sequence, so first substitute the
aromatic amine as you want, then make the diazo compound and heat it up with water:

NH
2
NaNO
2
aq. HCl
N
N
H
2
O
OH


Reactivity
Reactions of phenols can get a bit tricky. The main problem is that they react both as
highly activated aromatic rings, and as alcohols. Thus, with an acid chloride you can form an
ester. Or with methyl bromide and a base, you can form an ether:
OH
K
2
CO
3
CH
3
Br
OCH
3 OH
H
3
C
O
Cl
O
O
CH
3


The aromatic ring is also highly activated (as you might expect). Thus, with a
sufficiently good electrophile, the ring is easily substituted. However, since the lone pairs on
oxygen are not as hyperactive as those on nitrogen, it is usually easy to control the degree of
substitution:
OH
OH
OH
OH
Br
Br
Br
Br
Br
Br
Br
2
CCl
4
Br
2
/ HBr
1) Br
2
/ H
2
O
2) NaHSO
4

Carbon dioxide is also sufficiently electrophilic to react with phenols, and this is a great way to
prepare phenolic acids. Under normal conditions, the ortho isomer is formed. However, if the
product is heated under basic conditions, it isomerizes to the para isomer:
OH
K
2
CO
3
CO
2
150C
OH
O
-
O
240C
OH
O O
-
O
O
C
O
O
O
-
O
H
O
O
-
O
(proton transfer)


Some alkyl cations are also susceptible to addition to phenol. Frequently, these react
without the need of any metal catalysts (e.g. aluminum):
OH OH
H
2
SO
4
H
+
OH
OH
H

The aluminum catalyzed Friedel-Crafts reaction WILL NOT WORK WITH PHENOL.
However, if you simply protect the alcohol as an ether, Friedel Crafts reactions work QUITE
well:
OH
K
2
CO
3
CH
3
Br
OCH
3
O
O O
AlCl
3
OCH
3
O
OH
O

Oxidation of Phenols
Phenols undergo a rather unusual oxidation to compounds called quinones:

OH
(KSO
3
)
2
NO
H
2
O
O
O

The oxidation of a phenol (monohydroxybenzene) to a quinone requires rather harsh
conditions (Fremys salt). However, ortho and para dihydroxybenzenes oxidize to quinones
VERY easily. They are also easily reduced back to the dihydroxybenzene:

OH
O
O
OH
(KSO
3
)
2
NO
H
2
O
O
HO
OH
O
Na
2
Cr
2
O
7
SnCl
2
NaBH
4


The Claisen Rearrangement
Okay, time to look at electrocyclic stuff again. Allyl phenyl ethers rearrange in a rather
unique way:
O
O
An Allyl Phenyl Ether
O
H
OH
OH
1) NaH
2) BrCH
2
CHCH
2

This rearrangement involves a 6-membered ring intermediate, and pushes 6 electrons in a
circle. The initial result is a cyclic ketone, which rapidly tautaumerizes to regain aromaticity.
This is generally a good method for the preparation of phenols with allyl groups substituted on
the ring.
This rearrangement is kinda cool, but what happens if both positions ortho to the hydroxy
group are blocked? The allyl group then migrates again, to the para position!

O O O
H
OH

Be sure you understand the stereo and regiochemistry of this reaction . . .