In organic chemistry, alkynylation is an addition reaction in which a terminal alkyne () is added to a carbonyl group () to form an propargylic alcohol ().
When the acetylide is formed from acetylene (), the reaction gives an α-ethynyl alcohol. This process is often referred to as ethynylation. Such processes often involve metal acetylide intermediates.
Scope
The principal reaction of interest involves the addition of the
acetylene () to a
ketone () or
aldehyde ():
- RR'C=O + HC#CR -> RR'C(OH)C#CR
The reaction proceeds with retention of the
triple bond. For aldehydes and unsymmetrical ketones, the product is
chiral, hence there is interest in asymmetric variants. These reactions invariably involve metal-
acetylide intermediates.
This reaction was discovered by chemist John Ulric Nef in 1899 while experimenting with reactions of elemental sodium, phenylacetylene, and acetophenone.
In the following reaction ( scheme 1), the alkyne proton of ethyl propiolate is deprotonated by N-Butyllithium at -78 °C to form lithium ethyl propiolate to which cyclopentanone is added forming a Alkoxy group. Acetic acid is added to remove lithium and liberate the free alcohol.
Modifications
Several modifications of alkynylation reactions are known:
-
In the Arens–van Dorp synthesis the compound ethoxyacetylene
-
The Isler modification is a modification of Arens–Van Dorp Synthesis where ethoxyacetylene is replaced by β-chlorovinyl ethyl ether and lithium amide.
Catalytic variants
Alkynylations, including the asymmetric variety, have been developed as metal-catalyzed reactions.
Various catalytic additions of alkynes to electrophiles in water have also been developed.
Uses
Alkynylation finds use in synthesis of pharmaceuticals, particularly in the preparation of
.
For example, ethynylation of 17-ketosteroids produces important
contraceptive medications known as
. Examples include drugs such as
Norethisterone,
Ethisterone, and
Lynestrenol.
of these compounds produces anabolic steroids with oral
bioavailability, such as
Norethandrolone.
Alkynylation is used to prepare commodity chemicals such as propargyl alcohol,
Reaction conditions
For the stoichiometric reactions involving
alkali metal or
alkaline earth acetylides, work-up for the reaction requires liberation of the alcohol. To achieve this
hydrolysis,
aqueous acids are often employed.
- RR'C(ONa)C#CR {} + \overset{acetic\, acid}{CH3COOH} -> RR'C(OH)C#CR{} + \overset{sodium\, acetate}{CH3COONa}
Common solvents for the reaction include , acetals, dimethylformamide,
Variations
Grignard reagents
of acetylene or alkynes can be used to perform alkynylations on compounds that are liable to
polymerization reactions via enolate intermediates. However, substituting
lithium for
sodium or
potassium acetylides accomplishes similar results, often giving this route little advantage over the conventional reaction.
Favorskii reaction
The Favorskii reaction is an alternative set of reaction conditions, which involves prereaction of the
acetylene with an
alkali metal hydroxide such as KOH.
The reaction proceeds through equilibria, making the reaction reversible:
-
HC#CH + KOH <=> HC#CK + H2O
-
RR'C=O + HC#CK <=> RR'C(OK)C#CH
To overcome this reversibility, the reaction often uses an excess of base to trap the water as .
Reppe chemistry
Chemist
Walter Reppe pioneered catalytic, industrial-scale ethynylations using acetylene with alkali metal and copper(I) acetylides:
These reactions are used to manufacture propargyl alcohol and butynediol.
See also
Alkyne coupling reactions
-
Sonogashira coupling
-
Glaser coupling
-
Cadiot–Chodkiewicz coupling
-
Castro–Stephens coupling
-
A3 coupling reaction
