9. Alkynes: An Introduction to 9. Alkynes: An Introduction to Organic SynthesisOrganic Synthesis

Why this chapter?Why this chapter?We will use alkyne chemistry to begin looking at general strategies used in organic synthesis

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AlkynesAlkynesHydrocarbons that contain carbon-

carbon triple bonds CC≡≡CCAcetylene, the simplest alkyne is

produced industrially from methane and steam at high temperature

Our study of alkynes provides an introduction to organic synthesis, the preparation of organic molecules from simpler organic molecules

•The general formula for the alkynes is CnH2n-2, the same as for cycloalkenes.

•The common name common name for the smallest alkyne, C2H2, is acetylene.

•Common names Common names of other alkynes are treated as its derivatives – for instance, the alkylacetylenes.

9.1 Naming Alkynes9.1 Naming Alkynes

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Naming Alkynes: IUPACNaming Alkynes: IUPAC•The IUPAC rules for naming alkenes also apply to alkynes with the ending “-yne” replacing –ene.

•A number indicates the position of the triple bond in the main chain.

Alkynes having the structure, RCCH are terminal, those with the structure RCCR’ are internal.

Substituents bearing a triple bond are alkynl groups:

-CCH is named ethynyl;

-CH2CCH is 2-propynyl (propargyl).

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Side chainsSide chains

In IUPAC nomenclature, a hydrocarbon containing both a double and a triple bond is called an alkenyne.

The chain is numbered starting at the end closest to either functional group. In the case of a tie, the double bond is given the lower number.

Alkynes containing a hydroxyl group are named alkynols. In this case, the –OH takes precedence over both double and triple bonds in numbering the chain.

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Examples:Examples:

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Examples:Examples:

Learning Check:Learning Check:

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Solution:Solution:

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2,5-Dimethyl-3-hexyne3,3-Dimethyl-1-butyne

3,3-Dimethyl-4-octyne 3,3,6-Trimethyl-4-heptyne

6-Isopropylcyclodecyne

2,4-Octadiene-6-yne

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9.2 Preparation of Alkynes: 9.2 Preparation of Alkynes: Elimination Reactions of DihalidesElimination Reactions of Dihalides

Treatment of a 1,2-dihalidoalkane with KOH or NaOH produces a two-fold elimination of HX

Vicinal dihalides are available from addition of bromine or chlorine to an alkene

Intermediate is a vinyl halide

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Br BrC C

Br

HH

C C HH

Br C CH

Br

Br

H

C CH

Br Br

H OH C C BrHOH C C Br

C C

A vicinal dibromide

trans-stilbene

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Mechanism:

C C

H3C

Cl

H

CH2 O

NH2CH3 C C CH2 O

H O HH

a vinylic halide

Which compound can most easily undergo Which compound can most easily undergo elimination to give an alkyne?elimination to give an alkyne?

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20% 20% 20%20%20%1. 2.

3.

4. 5.

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Electronic Structure of AlkynesElectronic Structure of Alkynes CC≡≡CC triple bond results from sp orbital on each C forming a sigma

bond and unhybridized pX and py orbitals forming π bonds.

The remaining sp orbitals form bonds to other atoms at 180º to C-C triple bond.

The CC≡≡C C bond is shorter and stronger than single or double Breaking a π bond in acetylene (HC≡CH) requires 318 kJ/mole (in

ethylene it is 268 kJ/mole)

Properties and Bonding in the Properties and Bonding in the AlkynesAlkynes

Alkynes are relatively nonpolar.

Corresponding alkynes, alkenes and alkanes have very similar boiling points.

Ethyne: sublimes at -84oC

Propyne: b.p. -23.2oC

1-Butyne: b.p. 8.1oC

2-Butyne: b.p. 27oC

Medium sized alkanes: distillable liquids

Alkynes polymerize easily, frequently with violence.

Ethyne is linear and has strong, short bonds.

The two carbons in ethyne are sp2 hybridized.

The bonds are diffuse and resemble a cylindrical cloud:

The strength of a C≡C triple bond is about 958 kcal mol-1 (229 kcal mol-1).

As with alkenes, the strength of the bonds is much weaker than that of the δ bond which gives rise to much of the chemical reactivity of the alkynes.

The CC bond length is 1.20 Å (C=C is 1.33 Å).

The C-H bond lengths are also shorter than in ethene due to the larger degree of s character in the sp hybrid bonds (as compared to sp2).

Alkynes are high-energy compounds.

Alkynes often react with the release of considerable amounts of energy (prone to explosive decomposition).

Ethyne has a heat of combustion of 311 kcal mol-1 which is capable of generating a flame temperature >2500o C, sufficient for use in welding torches.

The heats of hydrogenation of alkyne isomers can be used to determine their relative stabilities:

The greater relative stabililty of internal alkynes is due to hyperconjugation.

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9.3 Reactions of Alkynes: Addition of 9.3 Reactions of Alkynes: Addition of HX and XHX and X22Addition reactions of alkynes are similar to those of alkenes Intermediate alkene reacts further with excess reagentRegiospecificity according to Markovnikov

Electrophilic Addition Reactions of Electrophilic Addition Reactions of AlkynesAlkynes

Addition of hydrogen halides forms haloalkenes and geminal dihaloalkanes.

In an analogous reaction with alkenes, hydrogen halides add across alkyne triple bonds.

The stereochemistry of this reaction is typically anti, particularly when excess halide ion is used.

A second molecule of hydrogen halide may also add, following Markovnikov’s rule, producing a geminal dihaloalkane.

Terminal alkynes also react with hydrogen halide, again following Mrakovnikov’s rule, although it is difficult to limit the reaction to a single molecule of hydrogen halide.

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Addition of HX to Alkynes Addition of HX to Alkynes Involves Vinylic CarbocationsInvolves Vinylic Carbocations

Addition of H-X to alkyne should produce a vinylic carbocation intermediate◦ Secondary vinyl

carbocations form less readily than primary alkyl carbocations

◦ Primary vinyl carbocations probably do not form at all

Nonethelss, H-Br can add to an alkyne to give a vinyl bromide if the Br is not on a primary carbon

Anti-Markovnikov Additions to Triple Anti-Markovnikov Additions to Triple BondsBonds

Radical addition of HBr gives 1-bromoalkenes.

In the presence of light or other radical initiators, HBr can add to an alkyne by a radical mechanism in an anti-Markovnikov fashion. Both syn and anti additions are observed.

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Addition of Bromine and ChlorineAddition of Bromine and ChlorineInitial addition gives trans intermediateProduct with excess reagent is tetrahalide

Halogenation takes place once or twice.

Halogenation of alkynes proceeds through an isolatable intermediate vicinal dihaloalkene, to the tetrahaloalkane. The two additions are anti.

Example:Example:

What is the product of the following What is the product of the following reaction?reaction?

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20% 20% 20%20%20%

1. 2.

3.

4. 5.

HBr

excess

If propyne reacts with BrIf propyne reacts with Br22/H/H22O following the O following the patterns of electrophilic-addition mechanisms, patterns of electrophilic-addition mechanisms, which of the following is the expected product? which of the following is the expected product?

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20% 20% 20%20%20%1.2.

3.

4. 5.

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9.4 Hydration of Alkynes9.4 Hydration of AlkynesAddition of H-OH as in alkenes

◦ Mercury (II) catalyzes Markovinikov oriented addition◦ Hydroboration-oxidation gives the non-Markovnikov

product

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Mercury(II)-Catalyzed Hydration of Mercury(II)-Catalyzed Hydration of AlkynesAlkynes

Alkynes do not react with aqueous protic acids

Mercuric ion (as the sulfate) is a Lewis acid catalyst that promotes addition of water in Markovnikov orientation

The immediate product is a vinylic alcohol, or enol, which spontaneously transforms to a ketone

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Mechanism of Mercury(II)-Catalyzed Hydration Mechanism of Mercury(II)-Catalyzed Hydration of Alkynesof Alkynes

Addition of Hg(II) to alkyne gives a vinylic cation

Water adds and loses a proton

A proton from aqueous acid replaces Hg(II)

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Keto-enol TautomerismKeto-enol Tautomerism Isomeric compounds that can rapidily interconvert

by the movement of a proton are called tautomers and the phenomenon is called tautomerism

Enols rearrange to the isomeric ketone by the rapid transfer of a proton from the hydroxyl to the alkene carbon

The keto form is usually so stable compared to the enol that only the keto form can be observed

Mercuric ion-catalyzed hydration of alkynes furnishes ketones.

In a reaction catalyzed by mercuric ion, water can be added to alkynes to give enols, which then tautomerize to give ketones.

Hydration follows Markovnikov’s rule: Terminal alkynes give methyl ketones:

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Hydration of Unsymmetrical Hydration of Unsymmetrical AlkynesAlkynes If the alkyl groups at either end of the C-C

triple bond are not the same, both products can form and this is not normally useful

If the triple bond is at the first carbon of the chain (then H is what is attached to one side) this is called a terminal alkyne

Hydration of a terminal always gives the methyl ketone, which is useful

Symmetrical internal alkynes give a single carbonyl compound;

Examples:Examples:

Unsymmetrical systems give a mixture of products:

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Hydroboration/Oxidation of AlkynesHydroboration/Oxidation of AlkynesBH3 (borane) adds to alkynes to give a vinylic

boraneOxidation with H2O2 produces an enol that

converts to the ketone or aldehydeProcess converts alkyne to ketone or aldehyde

with orientation opposite to mercuric ion catalyzed hydration

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Comparison of Hydration of Terminal AlkynesComparison of Hydration of Terminal Alkynes

Hydroboration/oxidation converts terminal alkynes to aldehydes because addition of water is non-Markovnikov

The product from the mercury(II) catalyzed hydration converts terminal alkynes to methyl ketones

Which is the Which is the bestbest starting material to starting material to prepare 2-pentanone?prepare 2-pentanone?

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1. pentane2. 1-pentene3. 2-pentene4. 1-pentyne5. 2-pentyne

H2O, H2SO4

HgSO4

O

What is the structure of What is the structure of intermediate intermediate II??

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20% 20% 20%20%20%1. 2.

3.

4. 5.

BD3

THF

H2O2

NaOHI product

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9.5 Reduction of Alkynes9.5 Reduction of AlkynesAddition of H2 over a metal catalyst (such as

palladium on carbon, Pd/C) converts alkynes to alkanes (complete reduction)

The addition of the first equivalent of H2 produces an alkene, which is more reactive than the alkyne so the alkene is not observed

Catalytic hydrogenation of alkynes using hydrogen and a platinum or palladium on charcoal catalyst results in complete saturation.

Example:Example:

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Conversion of Alkynes to cis-AlkenesConversion of Alkynes to cis-AlkenesAddition of H2 using chemically deactivated

palladium on calcium carbonate as a catalyst (the Lindlar catalyst) produces a cis alkene

The two hydrogens add syn (from the same side of the triple bond)

Catalytic hydrogenation using a Lindlar catalyst (palladium precipitated on CaCO3, and treated with lead acetate and quinoline) adds only one equivalent of hydrogen in a syn process:

This method affords a stereoselective synthesis of cis alkenes from alkynes.

p. 268

Examples:Examples:

Used in the commercial synthesis of Vitamin A

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Conversion of Alkynes to trans-AlkenesConversion of Alkynes to trans-AlkenesAnhydrous ammonia (NH3) is a liquid below -33 ºC

◦ Alkali metals (Li or Na) (Li or Na) dissolve in liquid ammonia and function as reducing agents

Alkynes are reduced to trans alkenes with sodium or lithium in liquid ammonia

The reaction involves a radical anion intermediate

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Another representation of the mechanism:Another representation of the mechanism:

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The final alkene is stable to further reduction by this reagent.

The second electron transfer takes place faster than any cis/trans equilibrium of the alkenyl radical.

Sequential one-electron reductions of alkynes produce trans alkenes.

Reduction of alkynes using metallic sodium dissolved in liquid ammonia (dissolving-metal reduction) produces trans alkenes.

Examples:Examples:

2-Hexyne is allowed to react with Li in NH2-Hexyne is allowed to react with Li in NH33(liq). The (liq). The obtained product is treated with Clobtained product is treated with Cl22 in CCl in CCl44. Which . Which of the following isomer is main product?of the following isomer is main product?

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20% 20% 20%20%20%

1. 2.

3.

4. 5.

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9.6 Oxidative Cleavage of Alkynes9.6 Oxidative Cleavage of Alkynes Strong oxidizing reagents (O3 or KMnO4) cleave internal

alkynes, producing two carboxylic acids Terminal alkynes are oxidized to a carboxylic acid and

carbon dioxide Neither process is useful in modern synthesis – were used to

elucidate structures because the products indicate the structure of the alkyne precursor

Which compound Which compound cannotcannot serve as an serve as an immediateimmediate precursor to the synthetic target precursor to the synthetic target shown below?shown below?

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1. 2.

3.

4. 5.

H

OOH

D

target molecule

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9.7 Alkyne Acidity: 9.7 Alkyne Acidity: Formation of Acetylide AnionsFormation of Acetylide Anions

Terminal alkynes are weak Brønsted acids (alkenes and alkanes are much less acidic (pKa ~ 25. See Table 8.1 for comparisons))

Reaction of strong anhydrous bases with a terminal acetylene produces an acetylide ion

The sp-hybridization at carbon holds negative charge relatively close to the positive nucleus (Figure 8.5 in text)

Terminal alkynes are remarkably acidic.

Table 8-1, p. 271

9.1

The electronegativity of a carbon atom depends upon its

hybridization. The more ss character in its hybrid orbitals, the greater the electronegativity.

The acidity of a C-H bond is directly related to the electronegativity of the carbon atom:

Strong bases such as sodium amide in liquid ammonia, alkyllithiums and Grignard reagents can deprotonate terminal alkynes to the corresponding alkynyl anions.

Alkynyl anions can react as bases and nucleophiles, much like other carbanions.

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9.8 Alkylation of Acetylide Anions9.8 Alkylation of Acetylide AnionsAcetylide ions can react as nucleophiles as well as

bases (see Figure 8-6 for mechanism)Reaction with a primary alkyl halide produces a

hydrocarbon that contains carbons from both partners, providing a general route to larger alkynes

Preparation of Alkynes from Alkynyl Preparation of Alkynes from Alkynyl AnionsAnions

Terminal alkynyl anions will react with alkylating agents such as primary (1o) haloalkanes, oxacyclopropanes, and aldehydes or ketones.

Reaction with secondary and tertiary halides leads to elimination products.

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Limitations of Alkyation of Acetylide IonsLimitations of Alkyation of Acetylide IonsReactions only are efficient with 1º alkyl bromides and

alkyl iodidesAcetylide anions can behave as bases as well as

nucelophilesReactions with 2º and 3º alkyl halides gives

dehydrohalogenation, converting alkyl halide to alkene

Other reactions of alkynyl anions:

Which of the following Which of the following is notis not a reason for a reason for alkyne hydrogens to be more acidic than alkyne hydrogens to be more acidic than alkene hydrogens? alkene hydrogens?

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1. the lone pair on alkynyl anion has more s character

2. the alkynyl anion is more stable

3. the lone-pair electrons on alkynyl anion are closer to the nucleus

4. hybridization differences make the vinyl anion less stable

5. the alkynyl anion is resonance stabilized

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9.9 An Introduction to Organic Synthesis9.9 An Introduction to Organic Synthesis Organic synthesis creates molecules by designSynthesis can produce new molecules that are

needed as drugs or materialsSyntheses can be designed and tested to improve

efficiency and safety for making known moleculesHighly advanced synthesis is used to test ideas

and methods, answering challengesChemists who engage in synthesis may see some

work as elegant or beautiful when it uses novel ideas or combinations of steps – this is very subjective and not part of an introductory course

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Synthesis as a Tool for Learning Organic Synthesis as a Tool for Learning Organic ChemistryChemistry In order to propose a synthesis you must be

familiar with reactions◦ What they begin with◦ What they lead to◦ How they are accomplished◦ What the limitations are

A synthesis combines a series of proposed steps to go from a defined set of reactants to a specified product◦ Questions related to synthesis can include partial

information about a reaction of series that the student completes

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Strategies for SynthesisStrategies for Synthesis Compare the target and the starting materialConsider reactions that efficiently produce the

outcome. Look at the product and think of what can lead to it (Read the practice problems in the text)

Example◦ Problem: prepare octane from 1-pentyne◦ Strategy: use acetylide coupling

Naturally Occurring and Physiologically Naturally Occurring and Physiologically Active AlkynesActive Alkynes

Chamomile flower

Chrysanthemum

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Lower Amazon Indian arrowhead poison.

“Poison arrow frog” toxin

Naturally occurring antibiotic-antitumor agents.

Nonprescription hypnotic

Which of the following molecules Which of the following molecules cannotcannot be be synthesized from propyne using only one synthesized from propyne using only one reaction?reaction?

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3.

4.5.

Which reaction sequence would be best to Which reaction sequence would be best to carry out the following transformation?carry out the following transformation?

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1. HBr (1 equivalent) followed by Br2/CCl4

2. HBr (2 equivalents) followed by Br2/hv

3. Br2/CH2Cl2 (2 equivalents) followed by H2/Pd/C

4. Br2/CH2Cl2 (2 equivalents) followed by NaOH

5. Br2/H2O followed by HBr (2 equivalents)

Br

Br Br

Which reagents are best to carry out the Which reagents are best to carry out the following reaction?following reaction?

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1. BH3/THF followed by NaOH/H2O2

2. HgSO4/H2O/H2SO4

3. NaNH2 followed by CH3I followed by HgSO4/H2O/H2SO4

4. OsO4 followed by NaHSO3/H2O

5. KMnO4/H+ followed by CH3I

O

Double bonds can be made by elimination of HX with the help Double bonds can be made by elimination of HX with the help of base, or by elimination of H-OH with the help of acid. of base, or by elimination of H-OH with the help of acid. Similarly, triple bonds can be made by elimination of two HX Similarly, triple bonds can be made by elimination of two HX molecules with base, but they cannot be made by elimination molecules with base, but they cannot be made by elimination of two molecules of water with the help of an acid. What is the of two molecules of water with the help of an acid. What is the main reason for this failure?main reason for this failure?

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20% 20% 20%20%20%1. 1,2-Diols cannot be

protonated by acids.

2. In diols, water can be eliminated only with the help of a base.

3. Formation of a triple bond requires elimination of three molecules of water.

4. The intermediate carbocation is too unstable.

5. The intermediate enol tautomerizes to a carbonyl compound.

2-Butyne is allowed to react with H2-Butyne is allowed to react with H22 over the Lindlar over the Lindlar catalysts. The obtained product is treated with catalysts. The obtained product is treated with OsOOsO44/pyridine followed by NaHSO/pyridine followed by NaHSO33/H/H22O. Which of the O. Which of the following compounds is the end result of this sequence following compounds is the end result of this sequence of reactions?of reactions?

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1. 2.

3.

4. 5.

A reaction of propyne with HgA reaction of propyne with Hg2+2+ is run in methanol is run in methanol (CH(CH33OH) in the absence of water, but in the presence of OH) in the absence of water, but in the presence of a strong acid (Ha strong acid (H++) with a non-nucleophilic counterion. If ) with a non-nucleophilic counterion. If this reaction follows a typical mechanism of electrophilic this reaction follows a typical mechanism of electrophilic addition, what would be the expected product?addition, what would be the expected product?

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1. 2.

3.

4. 5.

Consider the carbocations shown below. Consider the carbocations shown below. Which carbocation is more stabilized Which carbocation is more stabilized and why?and why?

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20% 20% 20%20%20%H

H

H

H

H

H

HH

1. The vinyl cation is more stabilized due to resonance.

2. The vinyl cation is more stabilized because it is a stronger Lewis acid.

3. The vinyl cation is more stabilized because of hyperconjugation.

4. The ethyl cation is more stabilized due to a σ*C-H/p orbital interaction.

5. The ethyl cation is more stabilized due to a σC-H/p orbital interaction.