Organic Chemistry I (PHCM332)- WS2025
Tutorial 8
Alcohols, Ethers, Epoxides and Amines
By the end of this tutorial , the student will be able to:
Domain 1: Fundamental Knowledge
1-1- Competency Key Elements
1-1-2 Identify the basis of IUPAC nomenclature of various aliphatic compounds
1-1-4 Define principles of synthesis of different aliphatic compounds
1-1-5 Recognize the different functional groups and relative re-activities of various aliphatic
1-1-6 Distinguish the different types of isomerism especially stereo-isomerism
1-1-7 Analyze & interpret the outcome of different organic reactions
1-1-8 Use the proper pharmaceutical terms, abbreviations & symbols
Domain 2: Professional & Ethical Practice
2-2- Competency Key Elements
2-2-1 Select the appropriate method of synthesis of organic compounds
Domain 3: Pharmaceutical Care
N/A
Domain 4: Personal Practice
4-1- Competency Key Elements
4-1-1 Demonstrate critical thinking, problem-solving & decision-making abilities
4-1-2 Implement writing skills through taking notes in lectures and tutorials
4-1-3 Evaluate information from different sources to improve professional competence
4-2- Competency Key Elements
4-2-1 Communicate clearly by verbal means through tutorial discussions
Alcohols Amines
Synthesis Synthesis
Reactions Reactions
Properties
Ethers Epoxides
Synthesis Synthesis
Reactions
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Alcohols
Synthesis
Reactions
Properties
1. Rank the following alcohols in order of increasing acidity.
1 2 4 3
Inductive effect: transmission of charge (positive or negative) through the σ
bonds in a carbon chain
(-)-σ effect stabilizes the anion by delocalization
of the negative charge
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Alcohols (R-OH)
Bad leaving group
Why ?
OH
Nu
How to convert OH into a Good leaving group ?
One way
Convert an OH (bad leaving group ) into H2O ( Good leaving
group) by Protonation with (HI, HBr)
2ry , 3ry alcohol SN1 1ry alcohol SN2
- At higher temperatures with non-nucleophilic acids (H2SO4): elimination favored.
H2SO4
130 ◦C
2. 2-Methylcyclohexanol on treatment with HBr gives 1-bromo-1-
methylcyclohexane. Explain by mechanism.
SN1
Mechanism Carbocation rearrangement
1,2-Hydride shift
Remember that a carbocation will rearrange if rearrangement produces a more stable
carbocation
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Other way
Converting the alcohol into an intermediate (leaving group) that is readily
displaced by a nucleophile e.g. a halide ion. O
Cl S R (
using phosphorus tri-halide (PBr3)or thionyl chloride (SOCl2) or sulfonyl chloride
) O
SN2
Carbocation rearrangements can be avoided
3. Complete the following reactions :
H2SO4
130 ◦C
PBr3
SN2
SOCl2
SN2
NaCN
SN2
H2, raney Ni
1
0
Amines
Synthesis
Reactions
Amines (R-NH2)
R
R N R
R
1ry Amine 2ry Amine 3ry Amine Quaternary
ammonium
Amines act as nucleophiles in a number of different kinds of
reactions
[Link] a reaction sequence for the synthesis of n- butylamine applying
Synthesis of 1ry Amines
Answer
Direct Alkylation not suitable
Gabriel synthesis
The catalytic reduction of a nitrile forms a primary
amine
Check next slides
Direct Alkylation
Why is a direct alkylation of ammonia unsuitable?
It is difficult to stop
the reaction after a
single alkylation since
ammonia and primary,
secondary, and
tertiary amines have
similar re-activities.
How to synthesize 1ry amine with a good yield?
One way
Gabriel synthesis
This reaction involves alkylating phthalimide and then hydrolyzing the N-substituted phthalimide.
a) Gabriel synthesis (3 steps)
In Gabriel synthesis the resulting amine comprises the same number of
carbons atoms as the reacting alkyl halide.
Other way
The catalytic reduction of a nitrile forms a primary
amineA nitrile can be obtained from the reaction of cyanide ion with an alkyl halide.
b) a sequence of a cyanide displacement and a subsequent reduction starting from the
appropriate bromo-alkane
In cyanide displacement the resulting amine has one
extra carbon than the reacting alkyl halide.
Hofmann elimination
The leaving group in a Hofmann elimination reaction is a
quaternary ammonium
A Hofmann elimination reaction is an E2
reaction
5. Write a reaction sequence (3 steps) for the Hofmann elimination of
the following amine
The major alkene product is the one
obtained by removing a proton from the
adjacent carbon bonded to the greater
number of hydrogens.
What is the source
of hydroxide ?
The ammonium (NR3)+ is a good leaving group. Treatment with a base will lead
to E2 reactions, where we form an alkene. 18
Ethers
Synthesis
Ethers R-O-R
Williamson ether synthesis
is a nucleophilic substitution reaction (SN2).
Ethers are synthesized by the reaction of an alkyl halide with an
alkoxide ion.
6. Suggest the best synthesis for each of the following ethers
applying the Williamson ether synthesis.
When carrying out a Williamson ether synthesis
(a) The less hindered alkyl group should be provided by
the alkyl halide and the more hindered alkyl group
should come from the alkoxide.
First pathway
2ry SN2 /E2
Elimination as a major side
OR product
Second pathway
Better pathway
1ry SN2 only
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(b)
First pathway
Second pathway
No
Reaction
Aryl halides generally do not undergo substitution(SN2/ SN1)
reactions
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Epoxides
Synthesis
Reactions
Epoxides
Ethers in which the oxygen atom is incorporated into a three-membered ring are
called epoxides.
Epoxides undergo ring-opening reactions with a wide variety of
nucleophiles, because the strain in the three-membered ring is
relieved when the ring opens.
The site of nucleophilic attack on an unsymmetrical epoxide
Under acidic conditions Under neutral or basic conditions
(when the epoxide is protonated). (when the epoxide is not protonated)
The more substituted carbon is The less substituted carbon
more likely to be attacked. is more likely to be attacked.
7. Give the expected products of each of the following reactions.
Explain by mechanism.
(a)
Attack at less hindered carbon
When a nucleophile attacks an un-protonated epoxide, the reaction is a pure SN2 reaction. That is,
the bond does not begin to break until the carbon is attacked by the nucleophile. In this case, the
nucleophile is more likely to attack the less substituted carbon because the less substituted carbon is
more accessible to attack (It is less sterically hindered).
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(b)
Transition state
More stable carbocation
- Protonated epoxides are so reactive that they can be opened by poor nucleophiles, such
water as and alcohols.
- The reaction pathway is Partially SN1 and partially SN2 It is not a pure SN1 reaction
because a carbocation intermediate is not fully formed; it is not a pure SN2 reaction because
the leaving group begins to depart before the compound is attacked by the nucleophile.
The more substituted carbon is more likely to be attacked
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References
• Organic Chemistry, 2nd edition, Clayden.
• Organic Chemistry, 12th edition, Solomons.
• Organic Chemistry, 4th edition, Bruice.
• Organic Chemistry, 4th edition, Carey.
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