Pharmaceutical Organic Chemistry Alkynes

Pr.HARKAT

Alkynes
1. General

-Alkynes are hydrocarbons that have one or more triple bonds. Considered as derivatives of acetylene, they
are also called acetylenics.
- The general formula for an aliphatic monoacetylene is CnH2n-2.
-Monosubstituted acethylenes are called “true alkynes”.

2-Nomenclature

The nomenclature of alkynes follows the same rules as that of alkanes, replacing the ending ANE with the
ending YNE.
The numbering of the main chain (the longest chain that contains the triple bond) is done so that the
carbons that carry the triple bond have the lowest indices.

1 2 3 4 5 6 1 2 3 4 5 6 7 8 9
CH3-CH2-C C-CH2-CH3 CH3-CH2-C C-CH2-CH-CH2-CH-CH3
hex-3-yne CH3 CH3
6,8-diméthylnon-3-yne

3-Physical Properties

Weakly polar compounds, their physical properties are close to those of alkanes and alkenes.
They are insoluble in water and soluble in low polarity solvents
Their densities are lower than that of water.
Boiling points increase with carbon number.

Physical properties of alkenes

Name Boiling point Melting point density

Ethyne -84 -61

Propyne -23.2 -103
1-Butyne 8.1 -126 0.65
2-Butyne 27 -32 0.69
1-Pentyne 40.2 -106 0.69
2-Pentyne 56.1 -109 0.71
1-Hexyne 71.5 -132 0.71
2-Hexyne 84 -88 0.73
1-Heptyne 99.7 -81 0.73
1-Octyne 126.2 -79 0.74
1-Nonyme 150.8 -50 0.76
1-Decyne 174 -44 0.766

4-Preparation Methods

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4-1-Dehydrohalogenation of vicinal dihalides

The reaction consists of eliminating two molecules of HX (X=F, Cl, Br, I) from a vicinal
dihalide.
This method is widely used because the synthesis intermediates (dihalides) are easily obtained
by the action of halogens on alkenes.
The reaction is carried out in two stages, the first of which is easier: there is first elimination of
a first molecule of HX leading to a less reactive vinyl halide which requires harsher operating
conditions or stronger bases.

Dehydrohalogenation of a dihalide
X H
KOH KOH/alcool ou
R C C R R CX CH R R C
alcool C R
NaNH2/NH3 liquide
H X
X= Br, Cl

In the second step a stronger base such as sodium amide (NaNH2) more easily yields the alkyne.
The use of potash (KOH) or sodium amide (NaNH2) depends on the structure of the halogenated
derivative and that of the alkyne that we want to obtain because we often observe the migration
of the triple bond: sodium amide favors the formation of true alkynes while potash favors that
of substituted alkynes.

Dehydrohalogenation of 2,3-dibromobutane using NaNH2

Br H
NaNH2
H3C C C CH3 H3C CH2 C CH
en excès
H Br

We therefore obtain a true alkyne.

H
NaNH2
H3C C C CH2 H3C C C CH2 H3C
(1) C C CH2

NH3 NaNH2
H3C C C CH2 H3C CH C CH2 H3C CH
(2) (3) C CH

H3C NH3 NaN H2

CH C CH H3C CH2 C CH
(4) (5)

H3C H2O
CH2 C CNa H3C CH2 C CH
(6)

On the other hand, the use of potash (KOH) in an alcoholic medium promotes the formation of
substituted alkynes.

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Dehydrogenation of 2,3-dibromobutane using KOH

H H Br
KOH
H3C C C C H H3C CH2 C CH isomérisation
H3C C C CH3
Ethanol
H Br H

4-2-Dehydrohalogenation of geminal dihalides

The geminate dihalides prepared by the action of phosphorus pentachloride (PCl5) on the
carbonyl derivatives also undergo dehydrohalogenation under the same conditions of the
previous paragraph and lead to the same types of products.

Alkyne from a geminate dihalide

H H Cl
KOH
H3C C C C H H3C CH2 C CH isomérisation
H3C C C CH3
Ethanol
H H Cl

4-3-Dehalogenation of tetrahalogenated derivatives

Metals like zinc (Zn), magnesium (Mg) can strip two halogen molecules from a tetrahalide.

Alkyne from a tetrahalide

H Cl Cl
2 Zn
H3C C C C H H3C CH2 C CH
H Cl Cl

This reaction is used for the protection of the triple bond because tetrahalogenated derivatives
are easily prepared by the action of halogens on alkynes.

4-4-Action of metal acetylides on halogenated derivatives

This reaction converts small alkynes into larger alkynes. The commonly used metal acetylides
are sodium, lithium and magnesium derivatives obtained respectively by the action of sodium
amide in liquid ammonia, alkyllithium compounds or GRIGNARD reagents on terminal
alkynes.

It is limited to primary halides because for the others, elimination reactions are often observed.

Alkylation of a true alkyne

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NaNH2 CH3 CH2 Br

H3C CH2 C CH H3C CH2 C CNa
NH3 liquide

H3C CH2 C C CH2 CH3

Sodium amide, a strong base, removes the terminal acidic proton from the alkyne. The alkynyl
ion obtained is a nucleophile which gives a nucleophilic substitution reaction with the
brominated derivative.

4-5-Preparation of acetylene

Acetylene is industrially prepared by the action of water on calcium carbide, itself obtained by
the reaction of lime with carbon.

Industrial preparation of acetylene

3 C + CaO CaC2 + CO

CaC2 + 2 H2O HC CH + Ca(OH)2

acéthylène
Another industrial method of preparing acetylene involves heating methane to 1500°C for a short
time.

1500°C
2 CH4 HC CH + 3 H2
0.01-0.1 sec.
acéthylène

5-Chemical Properties

5-1-Addition reactions

5-1-1-Catalytic hydrogenation

Alkynes can easily be hydrogenated to alkanes or alkenes. Commonly used catalysts are
platinum, palladium or nickel. All three catalysts are powerful enough to transform an alkyne
into an alkane. To achieve partial hydrogenation and stop at the alkene stage, palladium is
deactivated by adding quinoline.

Hydrogenation to alkanes

The catalyst is sufficiently active to lead directly to the alkane.

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H2
CH3-CH2-C C-CH2-CH3 CH3-CH2-CH2-CH2-CH2-CH3
Pt, Pd ou Ni

Hydrogenation to alkene using H2/Pd/BaSO4/Quinoleine

The catalyst being deactivated and furthermore the reaction is “cis” stereoselective, we obtain
an alkene of “cis” configuration when the triple bond is in the middle of the hydrocarbon
chain.

H5C2 C2H5
H2/BaSO4
CH3-CH2-C C-CH2-CH3 C C
quinolèine
H H
cisHex-3-ène

5-1-2-Reduction reactions
5-1-2-2-Reduction by a metal

The most used metal is sodium, dissolved in liquid ammonia. The reaction is stereoselective
“trans” and therefore leads to the “trans” alkene.

Reduction using sodium Na

H5C2 Br
Na, NH3 liquide
CH3-CH2-C C-CH2-CH3 C C
Br C2H5
transHex-3-ène
5-1-1-3-Hydroboration reaction

The addition of borane (BH3) or one of its derivatives to alkynes is a “cis” stereospecific
reaction. Furthermore, the reaction is regioselective and with an asymmetric alkyne, we obtain
the anti-MARKOVNIKOV addition product.
The intermediate vinylborane, treated with hydrogen peroxide (H2O2) in a basic medium,
leads to an aldehyde, if the triple bond is at the end of the chain, or to a ketone. The same
intermediate treated with a carboxylic acid gives an alkene.

Hydroboration of a terminal alkyne

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H5C2 H H5C2 H
BH3 R-CO2H
3 CH3-CH2-C CH C C 3 C C
( )3B H H
H

H2O2/OH

Tautomérie H5C2 H
3 CH3-CH2-CH2-C-H 3 C C
O H OH
Butanal
Enol

The mechanism of action of the H2O2/OH- couple has already been examined in alkenes

Hydroboration of a disubstituted alkyne

H5C2 CH3 H3C C2H5

BH3 C C
CH3-CH2-C C -CH3 C C +
( )3B ( )3B
H H

H2O2/OH

H5C2 CH3 H3C C2H5

C2H5-CH2-C-CH3 tautomérie
C C C C tautomérie
+ C2H5-C-C2H5
O H OH H OH
O
2-Pentanone
3-Pentanone

5-1-3-Halogenation

The addition of halogens (Cl2, Br2 and I2) is done in two steps; we first go through the
dihalogenated derivative: we can stop at this stage.

Addition of Br2 to a triple bond

Br Br
H5C2 Br
Br2, CH3CO2H Br2, CCl4
CH3-CH2-C C-CH2-CH3 C C CH3-CH2-C C-CH2-CH3
LiBr
Br C2H5 Br Br
trans-3,4-Dibromohex-3-ène 3,3,4,4-Tétrabromohexane
99% 95%

Due to steric hindrance, iodine leads only to the diiodinated derivative.

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5-1-4-Addition of hydracids

The reaction with hydracids (HX X=F, Cl, Br, I) leads in a first stage to a vinyl halide.
The addition of a second molecule gives a geminate dihalide.
The ionic addition on terminal alkynes follows the MARKOVNIKOV rule in both steps while
on a disubstituted alkyne only the second step proceeds according to this rule.

Addition of HCl to but-1-yne

H Cl H
CH3-CH2-C HCl HCl
CH CH3-CH2-C CH CH3-CH2-C CH
Cl Cl H
2,2-Dichlorobutane
Addition of HCl to pent-2-yne:
H CH3 Cl CH3
CH3-CH2-C C-CH3 HCl
C C + C C
H5C2 Cl H5C2 H

HCl

H Cl Cl H
H5C2 C C CH3 + H5C2 C C CH3
H Cl Cl H
2,2-Dicloropentane 3,3-Dichloropentane
The reaction may stop at the first stage.
The addition, in particular of hydrobromic acid, carried out in the presence of peroxides becomes
radical and leads to the anti-MARKOVNIKOV addition product.

Radical addition of HBr to an alkyne

Br H Br
HBr/RO-OR HBr/RO-OR
CH3-CH2-C CH CH3-CH2-C CH CH3-CH2-C CH
irradiation irradiation
H H Br
1,1-Dibromobutane
5-1-5-Hydration

The addition of water to a triple bond is catalyzed by mercury sulfate, in the presence of sulfuric
acid. The mercuric ion probably forms a complex with the acetylene; this will facilitate the attack
of H2O. We obtain ketones, with the exception of the hydration of acetylene which gives an
aldehyde.

Hydration of an alkyne
HgSO4/H2SO4
R C C R R C CH2 R
H2O
O

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Hg Hg
HgSO4/H2SO4 2+ H2O
R C C R R C C R R
(1) C C R
-H (2)
H OH
H tautomérie
R C C R R CH2 C R
(3) (4)
OH O
Enol Cétone

The mercuric ion complexes the alkyne, in the first step. This results in a bridged ion which
facilitates the attack of H2O, in the second step: when the triple bond is asymmetric, we end up
with an asymmetric intermediate and the reaction of H2O takes place on the most substituted
carbon because it further stabilizes the positive charge by the donor effect of alkyl radicals; the
global addition follows MARKOVNIKOV’s rule.
During the third step, an enol is formed, after destruction of the C-Hg bond, which tautomerizes
to finally obtain a carbonyl derivative.

Hydration of a terminal alkyne

HgSO4/H2SO4 tautomérie
CH3-CH2-C CH CH3-CH2-C CH2 CH3-CH2-C CH3
H2O
OH O
Butanone

Hydration of a dissubstituted alkyne

HgSO4/H2SO4
CH3-CH2-C C-CH3 CH3-CH2-C CH-CH3 + CH3-CH2-CH C-CH3
H2O
OH OH

tautomérie
CH3-CH2-C CH2-CH3 + CH3-CH2-CH2 C-CH3
O O
Pent-3-one Pent-2-one
50% 50%

5-2-Reactions of true alkynes

5-2-1-Acidity - Formation of acetylides
Bonded to a Sp carbon, the hydrogen of true alkynes is slightly acidic. This acidity is observed,
for example, in reactions with sodium or sodium amide.
Terminal alkynes also react with some heavy metals such as Ag+ and Cu+ to form insoluble
acetylides. This characteristic is used to locate the position of the triple bond in the hydrocarbon
chain: the formation of a precipitate after addition of an alkyne to an ammoniacal silver salt
solution is evidence that the alkyne is real.

Differentiation reactions between a true alkene and a disubstituted alkyne

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Ag(NH3)2
CH3-CH2-C CH CH3-CH2-C C-Ag
précipité insoluble

Ag(NH3)2 pas de réaction

CH3-C C-CH3

Copper acetylides are prepared by the action of cuprous chloride (Cu2 Cl2):
Cu2Cl2
CH3-CH2-C CH CH3-CH2-C C-Cu

Magnesium acetylides are obtained by an exchange reaction with an organomagnesium.

R-MgX
CH3-CH2-C CH CH3-CH2-C C-MgX

Sodium derivatives are prepared by the action of sodium amide in liquid ammonia.
NaNH2
CH3-CH2-C CH CH3-CH2-C C-Na

5-2-2-Nucleophilic substitution reactions

Metal acetylides are nucleophilic carbanions: they are capable of giving nucleophilic substitution
reactions with alkyl halides.

CH3-CH2-C CNa + CH3-CH2-CH2-Br CH3-CH2-C C-CH2-CH2-CH3

This type of reaction only applies to primary halides. With the others we observe elimination
reactions.

CH3-CH2-C CNa + CH3-CH-CH3 CH3-CH2-C C-CH-(CH3)2

Br + CH3-CH CH2
produit majoritaire

5-2-3-Nucleophilic addition reactions

Magnesium acetylides easily add to carbonyl derivatives to form alcohols, after acid hydrolysis
of the intermediate alkoxides.

Addition of a magnesium acetylide to a ketone

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CH3-CH2-C CMgX + CH3-C-CH3 CH3-CH2-C C-C(CH3)2

O OMgX
H2O
CH3-CH2-C C-C(CH3)2

OH

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