Overview

Introduction

Alkylation of terminal alkynes with primary alkyl halides in the presence of a strong base like sodium amide is one of the common methods for the synthesis of longer carbon-chain alkynes. For example, treatment of 1-propyne with sodium amide followed by reaction with ethyl bromide yields 2-pentyne.

The reaction takes place in two steps:

1. The first step is the deprotonation of the terminal alkyne by the strong base forming an acetylide ion.

2. The second step is a nucleophilic substitution reaction in which the acetylide ion reacts with the alkyl halide to form a new C–C bond.

Reaction Mechanism —S_N2 pathway

Acetylide ions are strong bases and can also function as good nucleophiles. The substitution reaction follows an S_N2 pathway where the nucleophilic acetylide ion attacks the electrophilic carbon of the primary alkyl halide from the backside.

Since this is a concerted process, the nucleophilic attack and the departure of the leaving group takes place simultaneously to form the product with an inverted stereochemistry at the reaction center.

The reaction works best with unhindered alkyl halides like methyl halide and other primary halides. With secondary and tertiary alkyl halides, acetylide ions act as strong bases, in which case E2 elimination is the preferred pathway.

Application in organic synthesis

Alkylation of simple terminal alkynes is a useful method to extend the length of the carbon chain. Acetylene, a terminal alkyne, can be converted to a higher internal alkyne by repeated alkylation as shown below:

Procedure

One of the two main approaches to preparing alkynes involves alkylation of terminal alkynes to form longer carbon-chain alkynes.

The preparation of alkynes using the alkylation approach proceeds in two steps.

The first step is a deprotonation reaction where a terminal alkyne reacts with a strong base like sodium amide to form the acetylide ion.

The second step is a substitution reaction in which the acetylide ion reacts with a primary alkyl halide to yield a longer carbon–chain alkyne.

Since a new alkyl group gets added to the starting alkyne, the reaction is called an alkylation reaction.

Recall that an acetylide ion is a strong base and can function as a strong nucleophile.

The substitution reaction follows an S_N2 mechanism in which the nucleophilic acetylide ion attacks the positively polarized carbon of the alkyl halide from a direction opposite to the halide leaving group.

This results in a transition state with a partially formed carbon–carbon bond and a partially broken carbon–halogen bond. The displacement of the leaving group yields the product with an inverted stereochemistry at the reaction center.

The S_N2 reaction is most efficient with unhindered alkyl halides like methyl halide and other primary alkyl halides, which are less sterically hindered allowing for the simultaneous nucleophilic attack and departure of the leaving group.

In contrast, with the bulky secondary and tertiary alkyl halides, acetylide ions act as strong bases and undergo an E2 elimination instead of substitution.

Alkylation of terminal alkynes is a useful method to synthesize longer carbon-chain alkynes. For example, deprotonation of acetylene and subsequent reaction with methyl bromide yields 1-propyne. This terminal alkyne can be further deprotonated and made to react with a different alkyl halide, like ethyl bromide, to form an internal alkyne, 2-pentyne.