Module L Terminal Alkyne Acidity:

Formation of Acetylide Anions

Alkynes:
An Introduction to Organic Synthesis  Terminal alkynes are weak Brønsted acids
 Alkenes and alkanes are much less acidic
Based on Bruice’s Organic Chemistry: Chapter 7

C CH
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: Terminal Alkyne Acidity:

Formation of Acetylide Anions Formation of Acetylide Anions

 Reaction of strong bases with a terminal acetylene produces an

acetylide anion

 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 Acidity of Terminal Alkynes
 Terminal alkynes have a relatively acidic proton
Increasing stability:
CH3CH2 - < CH2=CH - < HC≡C -
sp3has 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 6

Module L Reactions of Acetylides

Alkynes:  Because acetylides RC≡C- are readily generated, they can
be used in further reactions:
An Introduction to Organic Synthesis
Based on Bruice’s Organic Chemistry: Chapter 7
* 1° alkyl halide

 Mechanism:
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?
Terminal Strong base Substitution
alkyne deprotonates Sodium Internal + NaBr
alkyne acetylide + NH3 alkyne
7 8
 Simple Alkynes to Complex Alkynes Reactions of Acetylides
 Another example: *Cannot use 2° or 3° halides
for C-C bond formation

X
Methyl or
1o halide
 Mechanism:
Substitution

Example:
Sodium 2o or 3o
acetylide halide

An acetylide can react

Elimination
as a nucleophile to react with carbon
9 or a base to react with proton (deprotonation/elimination)
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Summary: Alkylation of Acetylides Module L

 An acetylide ion can react as a nucleophile (reacting with Alkynes:

carbon) or as a base (reacting with protons)
 React as a nucleophile with methyl or a primary alkyl halide: makes a new
An Introduction to Organic Synthesis
C-C bond, and is a general route to larger alkynes Based on Bruice’s Organic Chemistry: Chapter 7
 Reacts as a base with secondary and tertiary alkyl halides

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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 An Introduction to Organic Synthesis An Introduction to Organic Synthesis
 Organic  Synthesis can
produce new
synthesis
molecules from
produces target
simpler starting
molecules by
materials that are
design
Tamiflu needed as drugs
 Synthesis can or materials
produce new
molecules from
 All reactions are
important tools,
simpler starting
but the most
materials that are
important are
needed as drugs
those that make
or materials
new C-C bonds,
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An Introduction to Organic Synthesis

Reactions as Tools for Organic Synthesis
 All reactions are
important tools,
but the most
important are
those that make ⁎⁎
new C-C bonds,
as this is the only Starting material cannot have
way we can build another double bond or triple bond
up the carbon
framework of a
molecule  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 Strategies 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
 Look at the target molecule
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Strategies for Organic Synthesis 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
 This process of working backwards from the target
 Look at the product and ask yourself, “what reaction could molecule is called retrosynthetic analysis or retroanalysis
have made this?”
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 Strategies for Organic Synthesis Retrosynthetic Analysis
 Examine the target molecule
 Don’t start by thinking about: “What reactions can the The Nobel Prize in Chemistry 1990
starting material do?”
 Think instead about the reactions that produce the target Elias James Corey
molecule as a major product
USA
 Look at the product and ask yourself, “What reaction could
Harvard University
have made this?”
Cambridge, MA, USA
 This process of working backwards from the target
molecule is called retrosynthetic analysis "for his development of the theory and methodology of organic synthesis"

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Module L
Organic Synthesis Problem (I)
Alkynes:
An Introduction to Organic Synthesis
Based on Bruice’s Organic Chemistry: Chapter 7 H2/ Pd/ C

CH3CH2CH2C CCH2CH2CH3

Learning Outcomes: At the end of this module, you will learn: or

1. How to generate acetylides? CH3CH2CH2CH CHCH2CH2CH3

2. How to form C-C bonds using acetylides?
3. What is organic synthesis and retrosynthetic analysis?  Problem: prepare octane from 1-pentyne
4. How to sequence reactions to design multi-step synthesis of target molecules?  Solution: Look at target
 1. Octane (an alkane) can come from reduction of alkene or alkyne

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 Organic Synthesis Problem (I) Organic Synthesis Problem (I)

H2/ Pd/ C H2/ Pd/ C

CH3CH2CH2C CCH2CH2CH3 CH3CH2CH2C CCH2CH2CH3

or or

CH3CH2CH2CH CHCH2CH2CH3
 Solution: CH3CH2CH2CH CHCH2CH2CH3

 Solution:  5. Acetylide can be alkylated to generate 4-octyne.

 2. Compare SM and intermediate: a new C-C bond must be made with addition of 3 C
 6. Acetylide is easily generated from 1-pentyne.
 3. Suggests alkylation of acetylide.
 4. Alkyne as a precursor is more advantageous.
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Organic Synthesis Problem (I) Organic Synthesis Problem (II)

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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 SSA

Organic Synthesis Problem (II) Organic Synthesis Problem (III)

Must use correct catalyst!

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Organic Synthesis Problem (III) Organic Synthesis Problem (IV)

Retrosynthetic
arrow

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Organic Synthesis Problem (IV) Organic Synthesis Problem (V)

HBr

1-pentene

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Organic Synthesis Problem (V) Organic Synthesis Problem (VI)

or, Li in
liquid ammonia
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Organic Synthesis Problem (VI) 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 Summary

 We need to go beyond just making the  Similarities between the reactivities of alkenes and
alkynes in addition reactions
target molecule
 Preventing pollution at the molecular  But beware of issues of double addition
level: design new reactions that:  Addition of HX, X2
 Minimizes chemical wastes  Syn addition of H2 by partial hydrogenation, and anti
addition by dissolving metal reduction
 Uses less toxic reagents, solvents
 Addition of water (hydroboration-oxidation; acid-
 Are catalytic
catalyzed hydration; oxymercuration-demercuration)
 Result: sustainable future resulting in enols that tautomerize to keto compounds

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 Summary Course Learning Outcomes
 Differences in the reactivities of alkenes and alkynes:  Students who complete studies on Chapter 7 should be
terminal alkynes able to:
 Deprotonated to generate acetylides (electron density on
carbon)
 3. Understand the basic mechanism types: electrophilic
addition, SN1, SN2, E1, E2, and radical propagation
 Reacts with CH3- or 1º R-X as nucleophile to make C-C bond
mechanisms
 Reacts with 2º or 3º R-X as base
 Retrosynthetic analysis aids the planning  4. Apply the basic mechanisms to rationalize the
conditions and derive the outcomes of the reactions of
of organic synthesis
alkanes, alkyl halides, alkenes, dienes, alkynes, alcohols,
 Need to have a good grasp of all the ethers, epoxides, and organometallic compounds
reactions to increase the number of tools
in your synthesis toolbox  6. Apply reactions to the synthesis of target molecules
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