NTA Level 5 • Semester 1 • PST05106

Ethers of Pharmaceutical importance

Pharmaceutical Organic Chemistry • Source Session/Topic 15

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Session 15: Ethers 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 ethers

• List ethers and their isomers

• Explain nomenclature of ethers

• Draw chemical structure of ethers

• List chemical properties of ethers

• Explain chemical reactions of ethers

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 Ethers (10 minutes).

|Activity: Brainstorming (5 minutes) |

| |

|Ask students to brainstorm on the following question: |

| |

|What are Ethers? |

| |

|ALLOW few students to respond |

| |

|WRITE their responses on the flip chart/ board |

| |

|CLARIFY and SUMMARISE by using the content below |

• Ethers are compounds of formula R – 0 – R ', where R and R' may be alkyl

groups or aryl (benzene ring) groups.

• Ethers can be considered derivatives of water (HOH) or alcohols (ROH) by

replacing an H with an R group.

• In an alcohol, one hydrogen atom of water is replaced by an alkyl group.

• In an ether, both hydrogens are replaced by alkyl groups.

[pic]

• The R groups in ethers can be alkyl, aryl, or alkenyl.

• The R groups can be the same or different.

• If the R groups are the same, the ethers are called symmetrical ethers.

• If the R groups are different, the ethers are called unsymmetrical

ethers.

• Ethers can be cyclic or acyclic.

• Rings that contain an atom other than carbon are called heterocyclic

compounds.

• Oxygen is the heteroatom in cyclic ethers.

Examples of ethers

[pic]

• The most important commercial ether is diethyl ether, often called "ethyl

ether’’, or simply "ether."

STEP 3: Ethers and their Isomers (10 minutes).

Aliphatic Ethers can give two different types of isomers.

• Chain isomerism

o Ethers with the same formula and having different carbon chain

skeletons are called chain isomers.

o Examples:

[pic]

• Functional isomers.

o Ethers are isomeric with alcohols.

o Example:

[pic] is isomeric with ethyl alcohol C2H5OH

• Metamerism

o Isomers with the same molecular formula but different alkyl groups

(around the functional group) are called metamers. An ether with

formula C4H10O has 3 metamers.

[pic]

STEP 4: Nomenclature of Ethers (15 minutes).

• The IUPAC system, generally used with more complicated ethers, is

sometimes called the alkoxy alkane system.

• The common nomenclature of ethers, which is sometimes called the alkyl

alkyl ether system has also been widely used

• IUPAC names use the more complex alkyl group as the root name, and the

rest of the ether as an alkoxy group.

• For example, cyclohexyl methyl ether is named methoxycyclohexane.

• This systematic nomenclature is often the only clear way to name complex

ethers.

Example,

[pic]

|Table 1: Common Alkyl and Alkoxy Groups |

|CH3– |Methyl | |CH3O– |Methoxy |

|C6H5– |Phenyl | |C6H5O– |Phenoxy |

Common Names (Alkyl Alkyl Ether Names)

• Common names of ethers are formed by naming the two alkyl groups on

oxygen and adding the word ether.

• Under the current system, the alkyl groups should be named in

alphabetical order, but many people still use the old system, which named

the groups in order of increasing complexity.

• For example, if one of the alkyl groups is methyl and the other is t-

butyl, the current common name should be "t-butyl methyl ether,’’

• But most chemists use the older common name, "methyl t-butyl ether"

• If both groups are methyl, the name is "dimethyl ether.’’

• If just one alkyl group is described in the name, it implies the ether is

symmetrical, as in "ethyl ether."

STEP 5: Chemical Structure of Ethers (15 minutes).

• Ethers are a class of organic compounds that contain an ether group.

• An ether group is an oxygen atom connected to two alkyl or aryl groups.

• They follow the general formula R-O-R’. The C-O-C linkage is

characterized by bond angles of 104.5 degrees, with the C-O distances

being about 140 pm.

• The oxygen of the ether is more electronegative than the carbons.

• Thus, the alpha hydrogens are more acidic than in regular hydrocarbon

chains.

[pic]

STEP 6: Chemical Properties of Ethers (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 Ethers? |

| |

|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 |

• Ether are like alkanes, in that they undergo halogenation reactions.

• The oxygen of the ether linkage makes ethers basic, react with proton

donors to form oxonium salts.

• Ethers resist attack by nucleophiles and by bases.

STEP 7: Chemical Reactions involving Ethers (35 minutes).

|Activity: Small Group Discussion (15 minutes) |

| |

|DIVIDE students into small groups |

| |

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

|What are the chemical reactions involving Ethers? |

| |

|[pic]REFER Students to Book |

| |

|ALLOW students to discuss for 10 minutes |

| |

|ALLOW each group to present for 5 minutes |

| |

|CLARIFY and SUMMARIZE by using the contents below |

Reactions of Ether Due to an Alkyl Group

• Combustion: Ethers are highly inflammable, and they form extremely

explosive mixtures with air giving CO2 and water.

C2H5O C2H5 + 6O2 → 4CO2 + 5H2O

• Halogenation: The alkyl group undergoes substitution reaction with

chlorine or bromine. The resultant product is halogenated ether in

absence of sunlight. However, in presence of sunlight, it substitutes all

the hydrogen atoms of ethers.

CH3CH2OCH2CH3 [pic] CH3CHCIOCHCICH3 (α α’-dichloro diethyl ether)

CH3CH2OCH2CH3 [pic] C2CI2OC2CI5 (Perchloro diethyl ether)

Reaction of Ether Due to Ethereal Oxygen

• Ethers behave as Lewis bases because of the presence of two lone pairs of

electrons on the oxygen atom.

• Therefore, they form salts with strong acids.

• The oxonium salts are soluble in acid solution. We can facilitate the

regeneration of ether by hydrolysis of these salts.

• [pic]

Ethers also form coordination complexes with Lewis acids like BF3, AICI3,

RMgX etc.

• Therefore, we can derive the fact that ethers are very good solvents for

Grignard reagents.

Formation of Peroxides

• Ethers form peroxide linkage with oxygen when we expose them to air or

ozonized oxygen in presence of sunlight or ultraviolet light.

• These peroxides are highly poisonous in nature.

• They are oily liquids and decompose violently even at low concentrations.

• Therefore, we must ensure never to evaporate esters to dryness because it

might lead to explosive reactions.

• Besides this, we must also check the purity of ether before its use as an

anaesthetic agent.

• An impure ether (having peroxide linkage) gives red colour when shaken

with ferrous ammonium sulphate and potassium thiocyanate.

• This could prove to be lethal for the patients on whom we try

anaesthesia.

• [pic]

On mixing with KI solution, it liberates I2 which turns starch paper

blue.

[pic]

• We can make these ethers free from peroxide linkages by distilling

them with highly concentrated sulphuric acid, H2SO4.

• Also, we can check for the peroxide formation by adding a little

amount of Cu2O to the ether.

Reactions of Ether Involving Cleavage of Carbon-Oxygen Bond

• Action of dil. H2SO4: Ethers, on heating with dilute H2SO4, under high

pressure, hydrolyse to corresponding alcohols.

• Action of Conc. H2SO4: Ethers, on warming with conc. H2SO4, give alkyl

hydrogen sulphate.

R-OR + conc. H2SO4 → 2R HSO4

R-OR’ + conc. H2SO4 → RHSO4 + R’HSO4

• Action of HI:

• The products that we get during the action of HI on ethers depend

mainly upon the temperature in which we carry out the reaction.

• R-OR + HI [pic] R-OH + RI

• R-OR’ + HI [pic] R’-OH + RI

• Note: In case of a mixed ether, halogen atom attaches itself to the

simpler alkyl group.

• CH3OC2H5 + HI → CH3I + C2H5OH

• R-R + HI [pic] 2RI + H2O

We would observe similar reactions with HCI, HBr & the reactivity order is

HI > HBr > HCI.

• Action of PCI5: In the presence of heat, we get the following reaction:

R-O-R + PCI5 [pic] 2RCI + POCI3

• Action of Acetyl chloride or Acetic anhydride:

[pic]

• Dehydration of Ethers:

C2H5OC2H5 [pic] 2CH2=CH2 + H2

Action of Carbon Monoxide:

C2H5OC2H5, + CO [pic] C2H5COOC2H5

ROR + CO → RCOOR

STEP 8: Key Points (05 minutes).

• Ethers are a class of organic compounds that contain an ether group—an

oxygen atom connected to two alkyl or aryl groups.

• Ethers have the general formula R–O–R′, where R and R′ represent the

alkyl or aryl groups.

• Ethers can be named either by identifying the alkyl groups on either side

of the oxygen atom in alphabetical order, then write “ether” or by

using the formal, IUPAC method.

• Ethers have relatively low chemical reactivity, but they are still more

reactive than alkanes.

• Although they resist undergoing hydrolysis, ethers are often cleaved by

acids, which results in the formation of an alkyl halide and an alcohol.

• Ethers tend to form peroxides in the presence of oxygen or air.

STEP 9: Evaluation (05 minutes).

• What are ethers?

• List two ethers and their isomers?

• Draw chemical structure of ethers.

• What are chemical properties of ethers?

• List chemical reactions of ethers.

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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