NTA Level 5 • Semester 1 • PST05106

Amines of Pharmaceutical Importance

Pharmaceutical Organic Chemistry • Source Session/Topic 21

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Session 21: Amines 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 Amines

• Explain nomenclature of amines

• Draw chemical structure of amines

• List chemical properties of amines

• Explain chemical reactions of amines

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 Amines (10 minutes).

|Activity: Brainstorming (5 minutes) |

| |

|Ask students to brainstorm on the following question: |

| |

|What are Amines? |

| |

|ALLOW few students to respond |

| |

|WRITE their responses on the flip chart/ board |

| |

|CLARIFY and SUMMARISE by using the content below |

• Amines are organic derivatives of ammonia NH3 with one or more alkyl or

aryl groups bonded to the nitrogen atom.

• Amines contain a nitrogen atom with a lone pair of electrons; basic &

nucleophilic.

• Amines are present widely throughout both plants & animals.

• As a class amine include some of the most important biological compounds.

• Amines serve many functions in living organisms such as bioregulation,

neurotransmission, and defense against predators.

Examples of some biologically active amines

[pic]

STEP 3: Nomenclature of Amines (15 minutes).

• The IUPAC nomenclature for amines is similar to that for alcohols.

• The longest continuous chain of the carbon atoms determines the root

name.

• The -e ending in the alkane name is changed to -amine, and a number shows

the position of the amino group along the chain.

• Other substituents on the carbon chain are given numbers, and the prefix

N- is used for each substituent on nitrogen.

Examples

[pic]

Common Names

• Common names of amines are formed from the names of the alkyl groups

bonded to nitrogen, followed by the suffix –amine

• The pefixes di-, tri and tetra- are used to describe two, three, or four

identical substituents

Examples

[pic]

• In naming amines with more complicated structures, the -NH2 group is

called the amino group.

• The amino group is treated like any other substituent, with a number or

other symbol indicating its position on the ring or carbon chain.

Examples

[pic]

• Aromatic and heterocyclic amines are generally known by historical names.

• For example, phenylamine is called aniline, and its derivatives are named

as derivatives of aniline.

[pic]

Heterocyclic amines

• Compounds in which the nitrogen atom occurs as part of a ring.

• The heterocyclic nitrogen atom is always numbered as position 1.

Examples

[pic]

STEP 4: Chemical Structure of Amines (15 minutes).

• The basic chemical structure is that of ammonia (NH3) with the key atom

being the central nitrogen atom.

• The basic ammonia structure is changed when the hydrogen atoms are

replaced by alkyl groups to form amines.

• There are primary, secondary and tertiary amines.

|[pic] |

| |Secondary amine | |

| | | |

[pic]

Primary amine

[pic]

Tertiary amine

• The naming of amines is pretty straightforward. Primary amines are called

things like methylamine (CH3-NH2) and ethylamine (CH3-CH2-NH2).

• Simple secondary and tertiary amines are also easy to name. Dimethylamine

is CH3-NH-CH3 and trimethylamine is CH3-N(CH3)-CH3.

• Larger amines have names beginning with amino. For example, CH3-CH(NH)

-CH2-CH2-CH3 is called 2-aminopentane.

STEP 5: Chemical Properties of Amines (15 minutes).

|Activity: Buzzing (5minutes) |

| |

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

|minutes. |

| |

|What are the chemical properties of Amines? |

| |

|ALLOW pairs to respond on the question. |

| |

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

| |

|CLARIFY and SUMMARIZE by using the content below |

• They react with acids to form acid-base salts

• They react with electrophiles in polar reactions

• Amines are stronger bases than alcohols, ethers or water

• Kb (basicity constant) – used to measure the base strength of an amine

• Simple methylated amines are prepared by reaction of NH3 with CH3OH in

the presence of alumina catalyst.

STEP 6: Chemical Reactions involving Amines (45 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 Amines? |

| |

|[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 |

Due to the unshared electron pair, amines can act as both bases and

nucleophiles.

• Reaction with acids

When reacted with acids, amines donate electrons to form ammonium

salts.

[pic]

• Reaction with acid halides

o Acid halides react with amines to form substituted amides.

[pic]

o Aldehydes and ketones react with primary amines to give a reaction

product (a carbinolamine) that dehydrates to yield aldimines and

ketimines (Schiff bases).

[pic]

o If you react secondary amines with aldehydes or ketones, enamines

form.

[pic]

• Reaction with sulfonyl chlorides

o Amines react with sulfonyl chlorides to produce sulfonamides. A

typical example is the reaction of benzene sulfonyl chloride with

aniline.

[pic]

• The Hinsberg test

o The Hinsberg reaction is a lab test for the detection of primary,

secondary and tertiary amines.

o In this test, the amine is shaken well with Hinsberg reagent in the

presence of aqueous alkali (either KOH or NaOH).

o A reagent containing an aqueous sodium hydroxide solution

and benzenesulfonyl chloride is added to a substrate.

o A primary amine will form a soluble sulfonamide salt.

▪ Acidification of this salt then precipitates the sulfonamide of

the primary amine.

o A secondary amine in the same reaction will directly form an insoluble

sulfonamide.

o A tertiary amine will not react with the sulfonamide but is insoluble.

▪ After adding dilute acid this insoluble amine is converted to a

soluble Ammonium salt.

o In this way the reaction can distinguish between the three types of

amines.

[pic]

• Oxidation

o Although you can oxidize all amines, only tertiary amines give easily

isolated products.

o The oxidation of a tertiary amine leads to the formation of an amine

oxide.

[pic]

o Arylamines tend to be easily oxidized, with oxidation occurring on the

amine group as well as in the ring.

• Reaction with nitrous acid

o Nitrous acid is unstable and must be prepared in the reaction solution

by mixing sodium nitrite with acid.

o Primary amines react with nitrous acid to yield a diazonium salt,

which is highly unstable and degradates into a carbocation that is

capable of reaction with any nucleophile in solution.

o Therefore, reacting primary amines with nitrous acid leads to a

mixture of alcohol, alkenes, and alkyl halides

[pic]

o Primary aromatic amines form stable diazonium salts at zero degrees.

[pic]

o Secondary aliphatic and aromatic amines form nitrosoamine with nitrous

acid.

[pic]

o Tertiary amines react with nitrous acid to form N‐nitrosoammonium

compounds.

[pic]

Reactions of aromatic diazonium salts

• Diazonium salts of aromatic amines are very useful as intermediates to

other compounds.

• Because aromatic diazonium salts are only stable at very low temperatures

(zero degrees and below), warming these salts initiates decomposition

into highly reactive cations.

• These cations can react with any anion present in solution to form a

variety of compounds. Figure below illustrates the diversity of the

reactions.

[pic]

STEP 7: Key Points (05 minutes)

• Amines are organic derivatives of ammonia NH3 with one or more alkyl or

aryl groups bonded to the nitrogen atom

• The basic chemical structure is that of ammonia (NH3) with the key atom

being the central nitrogen atom

• Due to the unshared electron pair, amines can act as both bases and

nucleophiles

• The Hinsberg reaction is a lab test for the detection of primary,

secondary and tertiary amines

STEP 8: Evaluation (05 minutes)

• What are Amines?

• Classify amines

• Draw general chemical structure of tertiary amines

• List chemical properties of amines

• What is Hinsberg reaction?

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.

Nadendla R. R. (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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