Module L
Alkynes:
An Introduction to Organic Synthesis
Based on Bruice’s Organic Chemistry: Chapter 7
Learning Outcomes: At the end of this module, you will learn:
1. How to generate acetylides?
2. How to form C-C bonds using acetylides?
3. What is organic synthesis and retrosynthetic analysis?
4. How to sequence reactions to design multi-step synthesis of target molecules?
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Terminal Alkyne Acidity:
Formation of Acetylide Anions
Terminal alkynes are weak Brønsted acids
Alkenes and alkanes are much less acidic
C CH
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Terminal Alkyne Acidity:
Formation of Acetylide Anions
Reaction of strong bases with a terminal acetylene produces an
acetylide anion
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Terminal Alkyne Acidity:
Formation of Acetylide Anions
Reaction of strong bases with a terminal acetylene produces an
acetylide anion
Weaker acid Weaker base Stronger base Stronger acid
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Acidity of Terminal Alkynes
Terminal alkynes have a relatively acidic proton
Increasing stability:
CH3CH2 - < CH2=CH - < HC≡C -
sp3 has sp2 has acetylide
25% s 33% s sp-C has 50% s
Increasing acidity:
CH3—CH3 < CH2=CH2 < HC≡CH
Why? Increasing s-character of the carbon stabilizes negative
charge: the s orbitals holds negative charge close to the
positive nucleus 5
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Acidity of Terminal Alkynes
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Module L
Alkynes:
An Introduction to Organic Synthesis
Based on Bruice’s Organic Chemistry: Chapter 7
Learning Outcomes: At the end of this module, you will learn:
1. How to generate acetylides?
2. How to form C-C bonds using acetylides?
3. What is organic synthesis and retrosynthetic analysis?
4. How to sequence reactions to design multi-step synthesis of target molecules?
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Reactions of Acetylides
Because acetylides RC≡C- are readily generated, they can
be used in further reactions:
* 1° alkyl halide
Mechanism:
Terminal Strong base Substitution
alkyne deprotonates Sodium Internal + NaBr
alkyne acetylide + NH3 alkyne
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Simple Alkynes to Complex Alkynes
Example:
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Reactions of Acetylides
Another example: *Cannot use 2° or 3° halides
for C-C bond formation
X
Methyl or
1o halide
Mechanism:
Substitution
Sodium 2o or 3o
acetylide halide
An acetylide can react
Elimination
as a nucleophile to react with carbon
or a base to react with proton (deprotonation/elimination)
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Summary: Alkylation of Acetylides
An acetylide ion can react as a nucleophile (reacting with
carbon) or as a base (reacting with protons)
React as a nucleophile with methyl or a primary alkyl halide: makes a new
C-C bond, and is a general route to larger alkynes
Reacts as a base with secondary and tertiary alkyl halides
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Module L
Alkynes:
An Introduction to Organic Synthesis
Based on Bruice’s Organic Chemistry: Chapter 7
Learning Outcomes: At the end of this module, you will learn:
1. How to generate acetylides?
2. How to form C-C bonds using acetylides?
3. What is organic synthesis and retrosynthetic analysis?
4. How to sequence reactions to design multi-step synthesis of target molecules?
12
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An Introduction to Organic Synthesis
Organic
synthesis
produces target
molecules by
design
Tamiflu
Synthesis can
produce new
molecules from
simpler starting
materials that are
needed as drugs
or materials
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An Introduction to Organic Synthesis
Synthesis can
produce new
molecules from
simpler starting
materials that are
needed as drugs
or materials
All reactions are
important tools,
but the most
important are
those that make
new C-C bonds,
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An Introduction to Organic Synthesis
All reactions are
important tools,
but the most
important are
those that make
new C-C bonds,
as this is the only
way we can build
up the carbon
framework of a
molecule
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Reactions as Tools for Organic Synthesis
⁎⁎
Starting material cannot have
another double bond or triple bond
A synthesis combines a series of proposed steps to convert a
defined set of substrate/reagents to a specified product
(correct structure and stereochemistry) as the major product
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Reactions as Tools for Organic Synthesis
In order to propose a synthesis you must first have a good
knowledge of reactions
Know what the reactions begin with (starting materials or substrates)
Know what the reactions lead to (products)
Know how the reactions are accomplished (reagents, conditions)
Know what the reaction limitations are (compatibilities)
A synthesis combines a series of proposed steps to convert a
defined set of substrate/reagents to a specified product
(correct structure and stereochemistry) as the major product
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Strategies for Organic Synthesis
Look at the target molecule
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Strategies for Organic Synthesis
Don’t start by thinking about: “what reactions can the
starting material do?”
Think instead about the reactions that produce the target
molecule as a major product
Look at the product and ask yourself, “what reaction could
have made this?”
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Strategies for Organic Synthesis
This process of working backwards from the target
molecule is called retrosynthetic analysis or retroanalysis
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Strategies for Organic Synthesis
Examine the target molecule
Don’t start by thinking about: “What reactions can the
starting material do?”
Think instead about the reactions that produce the target
molecule as a major product
Look at the product and ask yourself, “What reaction could
have made this?”
This process of working backwards from the target
molecule is called retrosynthetic analysis
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Retrosynthetic Analysis
The Nobel Prize in Chemistry 1990
Elias James Corey
USA
Harvard University
Cambridge, MA, USA
"for his development of the theory and methodology of organic synthesis"
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Module L
Alkynes:
An Introduction to Organic Synthesis
Based on Bruice’s Organic Chemistry: Chapter 7
Learning Outcomes: At the end of this module, you will learn:
1. How to generate acetylides?
2. How to form C-C bonds using acetylides?
3. What is organic synthesis and retrosynthetic analysis?
4. How to sequence reactions to design multi-step synthesis of target molecules?
23
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Organic Synthesis Problem (I)
H2/ Pd/ C
CH3CH2CH2C CCH2CH2CH3
or
CH3CH2CH2CH CHCH2CH2CH3
Problem: prepare octane from 1-pentyne
Solution: Look at target
1. Octane (an alkane) can come from reduction of alkene or alkyne
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Organic Synthesis Problem (I)
H2/ Pd/ C
CH3CH2CH2C CCH2CH2CH3
or
CH3CH2CH2CH CHCH2CH2CH3
Solution:
2. Compare SM and intermediate: a new C-C bond must be made with addition of 3 C
3. Suggests alkylation of acetylide.
4. Alkyne as a precursor is more advantageous.
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Organic Synthesis Problem (I)
H2/ Pd/ C
CH3CH2CH2C CCH2CH2CH3
or
Solution: CH3CH2CH2CH CHCH2CH2CH3
5. Acetylide can be alkylated to generate 4-octyne.
6. Acetylide is easily generated from 1-pentyne.
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Organic Synthesis Problem (I)
If NaOH were used, the synthetic plan
The completed synthesis: would not be successful!
1-iodopropane or Must use correct
1-chloropropane catalyst!
can also be used!
1. Check the forward synthesis to make sure that all
reactions proceed as proposed, and that correct
reagents/conditions have been used. A correct
retroanalysis does not guarantee that the forward
synthesis is correct. A synthetic route is proved by
obtaining the target by following the route in the lab.
2. It is possible that there is more than one correct solution.
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Organic Synthesis Problem (II)
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Organic Synthesis Problem (II)
Must use correct catalyst!
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SSA
Organic Synthesis Problem (III)
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Organic Synthesis Problem (III)
Retrosynthetic
arrow
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Organic Synthesis Problem (IV)
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Organic Synthesis Problem (IV)
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Organic Synthesis Problem (V)
HBr
1-pentene
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Organic Synthesis Problem (V)
or, Li in
liquid ammonia
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Organic Synthesis Problem (VI)
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Organic Synthesis Problem (VI)
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The Art of Organic Synthesis
Using the same principles of
retrosynthetic analysis, highly
complex molecules can also
be synthesized
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Green Chemistry
We need to go beyond just making the
target molecule
Preventing pollution at the molecular
level: design new reactions that:
Minimizes chemical wastes
Uses less toxic reagents, solvents
Are catalytic
Result: sustainable future
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Summary
Similarities between the reactivities of alkenes and
alkynes in addition reactions
But beware of issues of double addition
Addition of HX, X2
Syn addition of H2 by partial hydrogenation, and anti
addition by dissolving metal reduction
Addition of water (hydroboration-oxidation; acid-
catalyzed hydration; oxymercuration-demercuration)
resulting in enols that tautomerize to keto compounds
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Summary
Differences in the reactivities of alkenes and alkynes:
terminal alkynes
Deprotonated to generate acetylides (electron density on
carbon)
Reacts with CH3- or 1º R-X as nucleophile to make C-C bond
Reacts with 2º or 3º R-X as base
Retrosynthetic analysis aids the planning
of organic synthesis
Need to have a good grasp of all the
reactions to increase the number of tools
in your synthesis toolbox
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Course Learning Outcomes
Students who complete studies on Chapter 7 should be
able to:
3. Understand the basic mechanism types: electrophilic
addition, SN1, SN2, E1, E2, and radical propagation
mechanisms
4. Apply the basic mechanisms to rationalize the
conditions and derive the outcomes of the reactions of
alkanes, alkyl halides, alkenes, dienes, alkynes, alcohols,
ethers, epoxides, and organometallic compounds
6. Apply reactions to the synthesis of target molecules
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