Review

Module K Structure of Alkynes

 Carbon-carbon triple bond is constructed from an sp orbital on
Alkynes: Electrophilic Additions each C to form a bond, and unhybridized px and py orbitals
forming 2 bonds
Based on Bruice’s Organic Chemistry: Chapter 7  The triple bond is shorter and stronger than single or double bonds:
breaking a  bond in acetylene (HC≡CH) requires 318 kJ/mol energy,
whereas ethylene (H2C=CH2) requires 268 kJ/mol
Learning Outcomes: At the end of this module, you will learn:

1. What is the structure of alkynes that account for their physical and chemical properties?
2. Which addition reactions of alkynes are direct mechanistic extensions of those of alkenes?
3. How to reduce alkynes to cis-alkenes, trans-alkenes, and alkanes? sp
4. How to convert alkynes to keto compounds via hydration? sp

Review

Electronic Structure of Alkynes Physical Properties of Alkynes

 The C sp–hybridization form bonds of 180º  Alkynes with more -electrons also have greater van der
Waals interactions

180o

3 4
 Review

Naming Alkynes Alkynes as substituents

 Number chain containing triple bond to give the smallest number to the triple
bond; give lowest numbers possible to other substituents
 An enyne has a double bond and triple bond  Alkynes as substituents are called alkynyl
 Select as the parent chain that which contains both double and triple bonds
 A compound with two or three triple bonds is a diyne or triyne
3

But-1-enyl But-1-ynyl

6-methylhepta-1,4-diyne

5 6

Terminology Module K

Alkynes: Electrophilic Additions

Based on Bruice’s Organic Chemistry: Chapter 7

Symmetrical Unsymmetrical Unsymmetrical

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

 Substituents stabilize alkynes, 1. What is the structure of alkynes that account for their physical and chemical properties?
2. Which addition reactions of alkynes are direct mechanistic extensions of those of alkenes?
just like for alkenes
3. How to reduce alkynes to cis-alkenes, trans-alkenes, and alkanes?
 Internal alkynes more stable 4. How to convert alkynes to keto compounds via hydration?
than terminal alkynes birth control

7
 Alkynes (and Alkenes) Reactions of Alkynes
 Alkynes react by addition to electrophiles—similar
electrophiles that also add to alkenes
 Addition of HX
 Addition of X2
 Addition of H2
 Addition of H2O
 Both are unsaturated molecules, having bonds  Acid-catalyzed hydration
 Oxymercuration
 Therefore, they undergo similar reactions  Hydroboration-oxidation
 Major differences?
9 10

Additions to Alkynes Reactions of Alkynes: Addition of HX

 Addition reactions of alkynes like those of alkenes
 Markovnikov addition occurs

 Electron-rich  bonds undergo electrophilic additions

 Each alkyne has two  bonds
 Additions can occur twice Limit to
 Each addition could have issues of regioselectivity and ~ 1 equiv
stereoselectivity
95% yield

11 12
 Reactions of Alkynes: Addition of HX Mechanism of Addition of HX
 Addition reactions of alkynes like those of alkenes
 Markovnikov addition occurs
 Intermediate alkene can react further with more reagent
 Markovnikov addition occurs again

geminal dibromide
gem- dibromide
13 14

More About Carbocations More About Carbocations

 Protonation of alkynes generate vinylic carbocations
 Protonation of alkynes generate “vinylic carbocations”
 Primary vinylic carbocations too unstable
 Some unstable vinylic carbocations may be -complexes
 Evidence: also (although not always) anti addition

 Secondary vinylic carbocations are about as stable as primary

alkyl carbocations– due to positive charge on sp-C

15 16
Stability and Reactivity of Alkynes Addition of HX to Alkynes
 Alkynes are less stable
than alkenes, but also
Stereochemistry: anti Stereochemistry: not selective
 Alkynes can add
one or two
less reactive in
Slower moles of HX
electrophilic additions Faster
 Each addition is
 Stability refers to Markovnikov
thermodynamics (Gº);
reactivity refers to  The second
kinetics (G‡) addition is
 Alkyne < stable than slower because

X X
alkene; but vinyl cation- the chloroalkene
is less electron
like TS is <<< stable than
rich
alkyl cation-like TS
18
17

Addition of X2 to Alkynes Reactions of Alkynes: Addition of X2

 X2 undergoes anti addition to alkynes  First addition is anti, gives trans dihaloalkene as intermediate
 Addition of one or two moles of X2  Two equivalents of X2 gives tetrahaloalkane as product

Br

19 20
EXERCISE 1 Module K

 Suggest synthetic routes to the following chloroalkanes, Alkynes: Electrophilic Additions

using any alkyne as starting materials. More than one step
may be needed. Based on Bruice’s Organic Chemistry: Chapter 7
Cl Cl

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

1. What is the structure of alkynes that account for their physical and chemical properties?
2. Which addition reactions of alkynes are direct mechanistic extensions of those of alkenes?
3. How to reduce alkynes to cis-alkenes, trans-alkenes, and alkanes?
4. How to convert alkynes to keto compounds via hydration?

21

Reduction of Alkynes Reduction of Alkynes

 It is possible to add only 1 equivalent of H2 to make alkenes
 This partial hydrogenation requires different catalysts

cannot stop here

 Reactive catalysts: Pt, or Pd on carbon Cis-alkene

 Same catalysts for reduction of alkenes to alkanes Syn addition

because H, H adds from
 Cannot stop at addition of 1 equivalent of hydrogen the catalyst surface

23 24
 Reduction of Alkynes to cis-Alkenes Reduction of Alkynes to cis-Alkenes
 Selecting the right catalyst determines the reduction  Reduction using Lindlar catalyst produces a cis-alkene,
outcome, not the amount of H2 used and double bonds are not reduced

25 26

Reduction of Alkynes to trans-Alkenes Reduction of Alkynes to trans-Alkenes

 Reduction of alkynes to make trans-alkenes  The dissolving metal reduction has a different stereochemical
is done by a “dissolving metal reduction” outcome, because it proceeds by a completely different
reaction, using Na or Li in liquid ammonia mechanism
 Anhydrous NH3 is a liquid below -33 ºC
 Alkali metals dissolve in liquid ammonia and
function as reducing agents (giving away
electrons)
 Alkenes are not reduced

ANTI addition

27 28
Reduction of Alkynes to trans-Alkenes Reduction of Alkynes to trans-Alkenes
 Mechanism: completely different!  Mechanism: completely different!
 Involves radicals, and single electron movement

NH2

radical anion

Notice the use of different arrows to show

electron or electron pair movement

29 30

Summary on Alkyne Additions (I) EXERCISE 2

 How to control additions to occur once or twice?  Suggest synthetic routes to the following molecules, using
 Addition of HX, X2/CCl4: control by the amount of reagent any alkyne as starting materials. More than one step may
be needed.

 Addition of H2: control by catalyst and reaction

31 32
 Module K
Hydration of Alkynes
Alkynes: Electrophilic Additions  Acid-catalyzed addition of water
Based on Bruice’s Organic Chemistry: Chapter 7

Learning Outcomes: At the end of this module, you will learn: KETONE
But these products
1. What is the structure of alkynes that account for their physical and chemical properties? (called ENOLS) are not isolated!
2. Which addition reactions of alkynes are direct mechanistic extensions of those of alkenes?
3. How to reduce alkynes to cis-alkenes, trans-alkenes, and alkanes?
4. How to convert alkynes to keto compounds via hydration?  An enol is formed but it is quickly converted to the more
stable ketone form
34

Hydration of Alkynes Hydration of Alkynes

 Terminal alkynes are less reactive towards protonation,  Addition of H-OH as in alkenes
so oxymercuration is used  Mercury (II) catalyzes Markovnikov addition
 Alkynes undergo oxymercuration to add water according  Hydroboration-oxidation gives anti-Markovnikov product
to Markovnikov’s rule
2-hexanone
KETONE
C4H9C CH
HO H ISOMERIZATION

C4H9 H O
C C H2C C hexanal
HO H ALDEHYDE
C4H9 H
ENOL ENOLS are not isolated
35
36
 Keto-enol Tautomerism Keto-enol Tautomerism
 An isomerization where constitutional isomers rapidly interconvert
is called a tautomerization; the isomers are called tautomers The isomerization is a change of the
 One important instance of tautomerism is the keto-enol -bond position and proton location
 We observe the keto form (ketone or aldehyde) as product because it
is usually the more stable form compared to the enol
 Keto-enol Tautomerization Mechanism under acid-catalyzed conditions:

37 38

Keto Enol Tautomerization EXERCISE 3

 Mechanism under acid-catalyzed conditions:
 Draw the alkyne precursors that were hydrated to give the
following enols. Convert them to the keto tautomers. Draw the
mechanism of tautomerization under acidic and basic conditions.
HO

OH
 Mechanism under base-catalyzed conditions:

OH

enolate 39 40
Mercury(II)-Catalyzed Hydration of Alkynes Comparison of Oxymercurations
 Alkene oxymercuration-demercuration
 Typically uses Hg(OAc)2

 Requires the addition of NaBH4 to induce demercuration
Hg(OAc)2 HgOAc NaBH4
tautomerization

H2O OH OH

tautomerization
 Terminal alkyne oxymercuration
 Typically uses more electrophilic HgSO4 because alkynes are less reactive
 Demercuration occurs in situ; separate step not required
 Water adds to the unsymmetrical mercurinium ion
 Demercuration occurs in the reaction (no additional reagent needed)
42
41

Hydroboration-oxidation of Alkynes Synthetically Useful Hydrations

an aldehyde

a methyl ketone

 For terminal alkynes, anti-Markovnikov and Markovnikov

hydrations generate different major products selectively
 Overall anti-Markovnikov addition of water to alkyne
43 44
 Synthetically Useful Hydrations EXERCISE 4
 Draw the mechanism to account for the product.

mixture of products — not useful

 For internal alkynes, there is no Markovnikov regioselectivity

 Only the hydration of symmetrical alkynes result in single
product and not a mixture
46
45

EXERCISE 5:
Summary on Alkyne Additions (II)
Can these compounds be obtained as major products starting
 How to control additions to occur once or twice for alkynes? from alkynes? If so, suggest the reagents and conditions.
 Addition of HX, X2: control by the amount of reagent
 Addition of H2: control by catalyst and method
 Addition of H2O or X2 / H2O: does not add twice due to rapid
conversion of enol to keto compound

47
48
 Module K
Summary of Alkyne Addition Reactions
 Similarities between the reactivities of alkenes and alkynes in Alkynes: Electrophilic Additions
electrophilic additions
 Similar reaction mechanisms Based on Bruice’s Organic Chemistry: Chapter 7
 Beware of issues of double addition
 Addition of HX, X2/CCl4 Check that you have achieved these learning outcomes, and can give
 Syn addition of H2 by partial hydrogenation, anti addition by examples to explain and answer each of these questions:
dissolving metal reduction, full reduction using reactive catalysts 1. What is the structure of alkynes that account for their physical and chemical properties?

 Addition of water (acid-catalyzed hydration, X2/H2O, 2.

3.
Which addition reactions of alkynes are direct mechanistic extensions of those of alkenes?
How to reduce alkynes to cis-alkenes, trans-alkenes, and alkanes?
oxymercuration, hydroboration-oxidation) generate enols that 4. How to convert alkynes to keto compounds via hydration?
tautomerize to keto compounds
49
 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?

1 2

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

3 4
 Acidity of Terminal Alkynes 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 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)
10

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?

11 12
 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,
13 14

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

15 16
 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
17 18

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?”
19 20
 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"

21 22

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

23 24
 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.
25 26

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.

27 28
 SSA

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

Must use correct catalyst!

29 30

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

Retrosynthetic
arrow

31 32
Organic Synthesis Problem (IV) Organic Synthesis Problem (V)

HBr

1-pentene

33 34

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

or, Li in
liquid ammonia
35
36
Organic Synthesis Problem (VI) The Art of Organic Synthesis
 Using the same principles of
retrosynthetic analysis, highly
complex molecules can also
be synthesized

37 38

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

40
39
 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
41
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