NTA Level 5 • Semester 1 • PST05106

Aromatic Organic Compounds of Pharmaceutical Importance

Pharmaceutical Organic Chemistry • Source Session/Topic 18

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Session 18: Aromatic Organic Compounds of Pharmaceutical Importance .

Total Session Time: 120 minutes

Prerequisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define aromatic organic compounds

• List aromatic compounds and their isomers

• Explain nomenclature of aromatic organic compounds

• Draw chemical structure of aromatic organic compounds

• List chemical properties of aromatic organic compounds

• Explain chemical reactions of aromatic organic compounds

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

SESSION OVERVIEW

SESSION CONTENTS.

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes).

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing.

STEP 2: Definition of Aromatic Organic Compounds (10 minutes).

|Activity: Brainstorming (5 minutes) |

| |

|Ask students to brainstorm on the following question: |

| |

|What are Aromatic Organic Compounds? |

| |

|ALLOW few students to respond |

| |

|WRITE their responses on the flip chart/ board |

| |

|CLARIFY and SUMMARISE by using the content below |

Aromatic hydrocarbons are those compounds that have molecular structures

based on that of benzene C6H6 & resemble benzene in chemical behaviour.

[pic]

The Kekule Benzene structure

• It suggests the presence of alternating single & double bonds.

• Kekule suggested that 2 forms of benzene were in rapid equilibrium.

[pic]

STEP 3: Aromatic Organic Compounds and their Isomers (15 minutes).

|Activity: Buzzing (10minutes) |

| |

|ASK students to pair up and buzz on the following question for 5 |

|minutes |

| |

|What are the isomers of Aromatic organic compounds? |

| |

|ALLOW pairs to respond on the question. |

| |

|WRITE their response on the flip chart/board. |

| |

|CLARIFY and SUMMARIZE by using the content in the table 1 below |

• In a disubstituted benzene, three different position isomers are possible

depending upon the position of one substituent with respect to the other.

• Ortho (o−) is used to indicate that the relative position of the two

substituents is 1,2−. Similarly, meta (m−) and para (p−) are used to

indicate the relative positions 1,3− and 1,4− respectively.

ortho, meta and para isomers of dimethylbenzene (xylene)

[pic]

STEP 4: Nomenclature of Aromatic Organic Compounds (15 minutes)

• For many of the derivatives we simply prefix the name of the substituent

group to the word benzene.

• Other derivatives have special names, which show no resemblance to the

name of the attached substituent group.

[pic]

STEP 5: Chemical Structure of Aromatic Organic Compounds (15 minutes)

• Aromatic compounds are cyclic structures in which each ring atom is a

participant in a bond, resulting in delocalized electron density on both

sides of the ring.

• Due to this connected network of bonds, the rings are planar, unlike the

boat or table structures typical of cycloalkanes.

Structure of benzene: resonance theory

• “Whenever 2 or more structures can be written for a molecule and the only

difference between the structures is in the position of electrons.”

[pic]

• If two groups are attached to the benzene ring their relative position

must be indicated. The three possible isomers of di-substituted benzene

are differentiated by use of the names;

o ortho-(o) at carbon 1 & 2,

o meta-(m) at carbon 1 & 3

o para-(p) at carbon 1 &4

[pic]

• If the two groups are different, and neither gives a common name, the two

groups are named successively, and the name is ended with –benzene:

• When benzene ring is a substituent, it is named as the prefix “phenyl”.

[pic]

STEP 6: Chemical Properties of Aromatic Organic Compounds (10 minutes).

|Activity: Brainstorming (5 minutes) |

| |

|Ask students to brainstorm on the following question: |

| |

|What are chemical properties of Aromatic Organic Compounds? |

| |

|ALLOW few students to respond |

| |

|WRITE their responses on the flip chart/ board |

| |

|CLARIFY and SUMMARISE by using the content below |

• Properties of Aromatic Hydrocarbons include that their major sources are

Petroleum and coal.

o Poly-aromatic hydrocarbons are defined as aromatic compounds with

more than one benzene.

o When they include in atmospheric pollution then it is known as

carcinogenic in nature.

• They go through electrophilic substitution reactions and nucleophile

aromatic substitution.

• Hydrocarbons which have multiple bonds are unsaturated in nature like

alkenes and alkynes.

o They tend to give addition reactions due to this unsaturation.

• Due to resonance and give characteristic electrophilic substitution

reactions aromatic hydrocarbons are stable.

o The carbon ring acts as a nucleophile in these reactions and to

form a substituted product an electrophile attack on benzene.

• With the coming electrophile, one of the H-atom of a ring is substituted

because of this the product also holds its stability and aromatic in

nature.

o On the opposite side in the addition reactions, aromatic compound

may lose their aromaticity, so they do not prefer to give such

reactions.

STEP 7: Chemical Reactions and Uses of Aromatic Organic Compounds (40

minutes).

|Activity: Small Group Discussion (20 minutes) |

| |

|DIVIDE students into small groups. |

| |

|ASK students to discuss in groups on the following questions. |

|What are the chemical reactions involving Aromatic Organic Compounds? |

| |

|[pic]REFER Students to Book |

| |

|ALLOW students to discuss for 15 minutes. |

| |

|ALLOW each group to present for 5 minutes. |

| |

|CLARIFY and SUMMARIZE by using the contents below |

Reactions with Substituent Effects

• Electrophilic Aromatic Substitutions

[pic]

• In an EAS reaction, an electrophile reacts with an aromatic ring and

substitutes it for one hydrogen.

General Mechanism

[pic]

There are five types of EAS reactions

o Halogenation

o Nitration

o Sulfonation

o Friedel-Crafts Alkylation

o Friedel-Crafts Acylation

o Nitration

▪ Reagents are HNO3 and H2SO4 with the electrophile being NO2+

[pic]

o Sulfonation

▪ Reagents are SO3 and H2SO4 (fuming sulfuric acid) with the

electrophile being HSO3+

[pic]

o Halogenation

▪ Reagents are X2 and FeX3 (catalyst) where X is a halogen

(generally Cl or Br)

[pic]

o Friedel-Crafts Alkylation

▪ Reagents vary, as there are three ways to produce the

electrophile—a carbocation; the overall reaction remains the same.

▪ Because this requires the formation of carbocation,

rearrangements are always possible.

R-X and AlX3 where X is either Br or Cl

[pic]

o Friedel-Crafts Acylation

▪ Reagents are an acyl halide (R-C=O-X) and AlX3 in which the

electrophile is R-C=O+

[pic]

▪ The acylation procedure can be used to produce alkyl benzenes

that otherwise cannot be prepared directly by alkylation through

Clemmensen Reduction.

▪ All that is required is the reduction of the acyl carbonyl group

to a CH2.

▪ The following is the Clemmensen Reduction reaction

[pic]

▪ The reagents used are a zinc/mercury amalgam and aqueous

hydrochloric acid.

▪ Therefore, to synthesize n-propyl benzene (which we could not do

via direct FC alkylation), acetalization using propanoyl chloride

can be done, and then reduce the phenyl ketone product which gives

our final product.

[pic]

The Benzene Elimination Addition Mechanism

• The previous addition elimination reaction mechanism required powerfully

electron withdrawing groups on the benzene ring.

• However, under forcing conditions, unactivated halobenzenes can react

with strong bases.

[pic]

• For example, phenol is produced commercially via the reaction of sodium

hydroxide with chlorobenzene.

• Analogously, aniline is produced via reaction of chlorobenzene with

sodium amide.

[pic]

• A clue to the mechanism of this type of reaction was provided by the

below reaction:

[pic]

• The products were found to be a 50:50 mixture of meta and para

substituted compounds.

• These two isomers can be explained as coming from the same intermediate,

a Benzyne.

Addition reactions of benzene

Although substitution is by far the most common reaction type of benzene

and its derivatives, addition reactions can occur if forcing conditions are

employed.

• Chlorination

o For example, if benzene is treated with an excess of chlorine under

conditions of heat and pressure, then 6 chlorine atoms will add,

generating 1,2,3,4,5,6-hexachlorocyclohexane.

[pic]

o This is believed to proceed through free radical intermediates, but

the mechanism is not relevant here.

• Catalytic Hydrogenation

o The addition of hydrogen to benzene occurs at elevated temperatures

and pressures, and requires a catalyst

[pic]

o Intermediate unsaturated compounds like cyclohexene or dienes

cannot be prepared because of the high pressures involved

Reactions of the Side Chains in Benzene Derivatives

• Permanganate Oxidation

o An aromatic ring imparts extra stability to the carbon atoms directly

bonded to it.

o Therefore, when an alkyl benzene is oxidized with permanganate, the

product is the carboxylate salt of di-benzoic acid.

[pic]

• Side Chain Halogenation

o Alkyl benzenes undergo free radical halogenation very easily at the

benzylic position, since the required intermediate radical is a

benzylic radical, and is therefore resonance stabilized

o For example, ethylbenzene reacts with bromine (or NBS) under UV

irradiation to give (1-bromoethyl)benzene and (1,1-

dibromoethyl)benzene.

[pic]

Uses of aromatic hydrocarbons

• In several industries, aromatic hydrocarbons have wide applications.

o For example, for model glues, toluene is used as solvent while

naphthalene is used as mothballs.

• For manufacturing of dyes, explosives, and drugs, Phenanthrene is an

intermediate product which has a different synthetic process.

o Trinitrotoluene (TNT) or 2, 4, 6 trinitrotoluene is an important

aromatic compound which is mainly used as explosive along with

the preparation of explosive.

• 1, 2 benzenediols or pyrocatechol is advertised as catechol which is

one of the most important components of a photographic developer.

STEP 8: Key Points (05 minutes).

• Aromatic compound, any of a large class of unsaturated chemical

compounds characterized by one or more planar rings of atoms joined

by covalent bonds of two different kinds.

• The unique stability of these compounds is referred to as aromaticity.

• Benzene (C6H6) is the best-known aromatic compound and the parent to

which numerous other aromatic compounds are related.

• The largest group of aromatic compounds are those in which one or more of

the hydrogens of benzene are replaced by some other atom or group, as

in toluene (C6H5CH3) and benzoic acid (C6H5CO2H).

• In the International Union of Pure and Applied Chemistry (IUPAC) system,

aromatic hydrocarbons are named as derivatives of benzene.

• The double bonds in aromatic compounds are less likely to participate in

addition reactions than those found in typical alkenes.

STEP 9: Evaluation (05 minutes).

• What are Aromatic organic compounds?

• Give three chemical structures of three different aromatic compounds

• What are the reactions involving aromatic organic compounds?

• What are the uses of aromatic organic compounds?

References

Ternay, A.L (1976). Contemporary Organic Chemistry. Philadelphia, United

States: W.B. Saunders Co.

Morrison R.T and Boyd R N (1997). Organic Chemistry (6th Ed.). New Delhi,

India: Prentice Hall of India

Graham Solomon et al (2014). Organic Chemistry (11th Ed.). New Jeysey,

United States: John Willey and Sons.

Rama Rao Nadendla (2005). Principles of Pharmaceutical Organic Chemistry.

New Delhi, India: MacMillan Publishers

Bruice Y (2013). Organic Chemistry (7th ed.). New York, United States:

Prentice Hall Pearson.

Delgado J. N. Et al (1998). Wilson and Gisvold's Textbook of Organic

Medicinal and Pharmaceutical Chemistry (10th Ed.). California, United

States: Lippincott Williams

Bhassin S.K, Gupta R.(2013). Pharmaceutical organic chemistry (E-book

Kindle edition). New Delhi, India: Elsevier Publishing Services

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