Aromatic, Benzenoid and Heterocyclic Chemistry
Aromatic, Benzenoid and Heterocyclic Chemistry
Aromatic, Benzenoid and Heterocyclic Chemistry
School of Pharmacy
Many derivatives of benzene were originally isolated from the fragrant balsams obtained from
trees and plants, and these compounds were therefore described as being aromatic in reference to
their pleasant odors. Over time, chemists discovered that many derivatives of benzene are, in
fact, odorless. Nevertheless, the term ―aromatic‖ is still used to describe all derivatives of
benzene, regardless of whether they are fragrant or odorless. All of the following top-selling
drugs contain the benzene-like aromatic ring (highlighted in red).
The molecular formula of this compound is C6H6: a hydrocarbon comprised of six carbon atoms
and six hydrogen atoms. In 1866, August Kekulé used his recently published structural theory of
matter to propose a structure for benzene. Specifically, he proposed a ring comprised of
alternating double and single bonds.
Kekulé described the exchange of double and single bonds to be an equilibrium process. Over
time, this view was refined by the advent of resonance theory and molecular orbital concepts of
delocalization. The two drawings above are now viewed as resonance structures, not as an
equilibrium process
2. Each atom in the ring must have an unhybridized p orbital. (The ring atoms are usually sp2
hybridized or occasionally sp hybridized.)
3. The unhybridized p orbitals must overlap to form a continuous ring of parallel orbitals. In
most cases, the structure must be planar (or nearly planar) for effective overlap to occur.
4. Delocalization of the pi electrons over the ring must lower the electronic energy.
The tendency of benzene to react by substitution rather than addition gave rise to another concept
of aromaticity. For a compound to be called aromatic meant, experimentally, that it gave
substitution reactions rather than addition reactions even though it was highly unsaturated.
In addition to those that we have seen so far, there are many other examples of aromatic
compounds. Benzene is not the only compound that exhibits aromatic stabilization.
Representatives of one broad class of benzenoid aromatic compounds, called polycyclic
aromatic hydrocarbons (PAH) are shown below:
NB
Compounds that do not contain a ring that comprised of continuously overlapping p orbitals are
called nonaromatic compounds.
Almost all of the cyclic molecules that we have discussed so far have had rings composed solely
of carbon atoms. However, in many cyclic compounds an element other than carbon is present in
the ring. • Cyclic compounds that include an element other than carbon are called heterocyclic
compounds.
Heterocyclic compounds containing nitrogen, oxygen, or sulfur are by far the most common.
Four important examples are given here in their Kekulé forms. These four compounds are all
aromatic:
Some of the most important reactions of aromatic compounds are those in which an electrophile
replaces one of the hydrogen atoms of the ring. These reactions, called electrophilic aromatic
substitutions (EAS), allow the direct introduction of groups onto aromatic rings such as
benzene, and they provide synthetic routes to many important compounds.
In this unit, we will see many other groups that can also be installed on an aromatic ring via an
electrophilic aromatic substitution reaction.
The sigma complex (also called an arenium ion) is not aromatic because the sp3 carbon atom
interrupts the ring of p orbitals. The sigma complex regains aromaticity either by a reversal of
the first step (returning to the reactants) or by loss of the proton on the tetrahedral carbon atom,
leading to the aromatic substitution product.
Benzene reacts with bromine and chlorine in the presence of Lewis acids to give halogenated
substitution products in good yield. The Lewis acids typically used are aluminum chloride
(AlCl3) and iron chloride (FeCl3) for chlorination, and iron bromide (FeBr3) for bromination. The
purpose of the Lewis acid is to make the halogen a stronger electrophile.
Bromination Mechanism
Sulfonation
Benzene reacts with fuming sulfuric acid at room temperature to produce benzene-sulfonic acid.
Fuming sulfuric acid is sulfuric acid that contains added sulfur trioxide (SO3). Sulfonation also
takes place in concentrated sulfuric acid alone, but more slowly. Under either condition, the
electrophile appears to be sulfur trioxide.
When benzene is treated with a mixture of nitric acid and sulfuric acid, a nitration reaction
occurs in which nitrobenzene is formed.
Concentrated sulfuric acid increases the rate of the reaction by increasing the concentration of
the electrophile, the nitronium ion (NO2+). The nitronium ion is formed from HNO3 by
+
protonation and loss of water and which reacts with benzene in much the same way Br does.
Attachment of an amino group to an aromatic ring by the two-step nitration/reduction sequence
is a key part of the industrial synthesis of many dyes and pharmaceutical agents
The mechanism for the reaction starts with the formation of a carbocation.
The carbocation then acts as an electrophile and is attacked by the benzene ring to form
an arenium ion.
The arenium ion then loses a proton.
Reaction Mechanism
A reaction that installs an acyl group is called an acylation. Two common acyl groups are the
acetyl group and the benzoyl group. (The benzoyl group should not be confused with the benzyl
group, −CH2C6H5
The Friedel–Crafts acylation reaction is often carried out by treating the aromatic compound
with an acyl halide (often an acyl chloride). Unless the aromatic compound is one that is highly
reactive, the reaction requires the addition of at least one equivalent of a Lewis acid (such as
AlCl3) as well. The product of the reaction is an aryl ketone:
Mechanism
Only one product can form when an electrophilic substitution occurs on benzene, but what would
happen if we were to carry out an electrophilic substitution on a ring that already has a
substituent? A substituent already present on the ring has two effects:
Substituents can be classified into three groups, as shown below: meta-directing deactivators,
ortho- and para-directing deactivators, and ortho and para-directing activators. There are
no meta-directing activators. Note how the directing effect of a group correlates with its
reactivity. All meta directing groups are deactivating, and all ortho- and para-directing groups
other than halogen are activating. The halogens are unique in being ortho and para-directing but
deactivating.
What makes a group either activating or deactivating? The common characteristic of all
activating groups is that they donate electrons to the ring, thereby making the ring more electron-
rich, stabilizing the carbocation intermediate, and lowering the activation energy for its
formation. Conversely, the common characteristic of all deactivating groups is that they
withdraw electrons from the ring, thereby making the ring more electron-poor, destabilizing the
carbocation intermediate, and raising the activation energy for its formation.
Let’s look at the nitration of phenol as an example of how ortho- and para directing substituents
work. In the first step, reaction with the electrophilic nitronium ion (NO2) can occur either ortho,
meta, or para to the OH group, giving the carbocation intermediates.
In general, any substituent that has a lone pair of electrons on the atom directly bonded to the
aromatic ring allows an electron-donating resonance interaction to occur and thus acts as an
ortho and para director.
The influence of meta-directing substituents can be explained using the same kinds of arguments
used for ortho and para directors. Look at the chlorination of benzaldehyde, for instance. Of the
three possible carbocation intermediates, the meta intermediate has three favorable resonance
forms, while the ortho and para intermediates have only two. In both ortho and para
intermediates, the third resonance form is particularly unfavorable because it places the positive
charge directly on the carbon that bears the aldehyde group, where it is disfavored by a repulsive
interaction with the positively polarized carbon atom of the C=O group. Hence, the meta
intermediate is more favored and is formed faster than the ortho and para intermediates.
In general, any substituent that has a positively polarized atom directly attached to the ring
makes one of the resonance forms of the ortho and para intermediates unfavorable, and thus acts
as a meta director.
Both activators and deactivators can be classified as strong, moderate, and weak.
Activators
Strong activators are characterized by the presence of a lone pair immediately adjacent to the
aromatic ring.
All of these groups exhibit a lone pair that is delocalized into the ring, as can be seen in their
resonance structures. For example, phenol has the following resonance structures:
Many of these resonance structures have a negative charge in the ring, indicating that the OH
group is donating electron density into the ring. This electron-donating effect strongly activates
the ring.
Moderate activators exhibit a lone pair that is already delocalized outside of the ring.
This effect diminishes the capability of the lone pair to donate electron density into the ring.
These groups are activating, but they are moderate activators. The lone pair of an alkoxy group
(OR) is not participating in resonance outside of the ring, and we might therefore expect that it
would be a strong activator. Nevertheless, alkoxy groups belong to the class of moderate
activators. Alkoxy groups are generally more activating than other moderate activators but less
activating than strong activators (such as amino groups).
Alkyl groups are weak activators, because they donate electron density by the relatively weak
effect of hyperconjugation.
Deactivator
As we have already seen, many of the halogens (Cl, Br, or I) are observed to deactivate a
benzene ring:
We have seen that the electronic effects of halogens are determined by the delicate competition
between resonance and induction, with induction emerging as the dominant effect. As a result,
halogens are weak deactivators.
Each of these groups withdraws electron density from the ring via resonance. For example:
Three of the resonance structures have a positive charge in the ring, indicating that the group is
withdrawing electron density from the ring. This electron-withdrawing effect moderately
deactivates the ring.
The nitro group is a strong deactivator because of resonance and induction. The other two groups
are strong deactivators because of powerful inductive effects. A positively charged nitrogen atom
is extremely electronegative, and CX3 has three electron-withdrawing halogens. Do not confuse a
CX3 group with a halogen (X).
In this section, we consider reactions in which the ring is attacked by a nucleophile. Such
reactions are called nucleophilic aromatic substitution reactions. In the following example, an
aromatic compound is treated with a strong nucleophile (hydroxide), which displaces a leaving
group (bromide):
In order for a reaction like this to occur, three criteria must be satisfied:
1. The ring must contain a powerful electron-withdrawing group (typically a nitro group).
3. The leaving group must be either ortho or para to the electron-withdrawing group. If the leaving group
is meta to the nitro group, the reaction is not observed.
Any mechanism that we propose for nucleophilic aromatic substitution must successfully explain
the three criteria.
2. The leaving group: In electrophilic aromatic substitution, the incoming substituent replaces a
proton. In the other two mechanisms, a negatively charged leaving group (such as a halide ion) is
expelled.
Pharmaceutical Application
Halogenation is a critical process in the design of many other types of drugs as well. For
example, consider the antifungal agents chlotrimazole and econazole:
Both of these compounds are examples of azole antifungal agents (azoles are a broad class of
five-membered rings that contain a nitrogen atom and at least one other heteroatom, such as
nitrogen, oxygen, or sulfur). Azole antifungal agents typically contain two or three additional
aromatic rings, at least one of which is substituted with a halogen. Structure-activity studies have
revealed that the presence of a halogen is critical for drug activity. Chlotrimazole is marketed
under the trade name Lotrimin, and econazole is marketed under the trade name Spectazole.
Notice that in both of these compounds the halogens are positioned in the ortho and para
positions.
Among many other applications, azo dyes are currently used in paints, cosmetics, and food. One
such application led to a discovery that had a profound impact on the field of medicine.
Specifically, it was observed that certain bacteria absorbed azo dyes, making them more readily
visible under a microscope. In an effort to find an azo dye that might be toxic to bacteria, Fritz
Mietzsch and Joseph Klarer (at the German dye company, I.G. Farbenindustrie) began
cataloguing azo dyes for possible antibacterial properties. A physician named Gerhard Domagk
evaluated the dyes for potential activity, which led to the discovery of the potent antibacterial
properties of prontosil.
Domagk was able to demonstrate that prontosil cured streptococcal infections in mice. In 1933,
physicians began using prontosil in human patients suffering from life-threatening bacterial
infections. The success of this drug was extraordinary, and prontosil staked its claim as the first
drug that was systematically used for the treatment of bacterial infections.
Prontosil exhibited one very curious property that intrigued scientists. Specifically, it was found
to be totally inactive against bacteria in vitro (literally ―in glass,‖ in bacterial cultures grown in
glass dishes). Its antibacterial properties were only observed in vivo (literally ―in life,‖ when
administered to living creatures, such as mice and humans). These observations inspired much
research on the activity of prontosil, and in 1935, it was found that prontosil is metabolized in the
body to produce a compound called sulfanilamide.
Some sulfonamides are still used today to treat specific bacterial infection in patients with AIDS,
as well as a few other applications. Despite their small role in current practice, sulfonamides
occupy a unique role in history, because their development was based on the discovery of the
first known prodrug.
Reference:
1. Klein, D. R. (2016). Organic Chemistry (4th ed.). John Wiley & Sons, Inc.
4. Solomons, G., Fryhle, C. B., & Snyder, S. A. (2016). Organic Chemistry. John Wiley & Sons