9.8 Alkylation of Acetylide Anions

Alkylation of Acetylide Anions

Acetylide anions with alkyl halides

Acetylide anions let you build longer carbon chains by forming new C–C bonds. They're one of the most reliable ways to construct internal alkynes in synthesis.

To make an acetylide anion, you deprotonate a terminal alkyne with a strong base like sodium amide ($\ce{NaNH2}$) or n-butyllithium ($\ce{n-BuLi}$). The base removes the terminal $\ce{sp}$-hydrogen, generating a carbanion with the negative charge on the $\ce{sp}$-hybridized carbon. Terminal alkynes have a pKa of about 25, which is acidic enough for these strong bases to deprotonate them but far too high for something like $\ce{NaOH}$ to do the job. The reason $\ce{sp}$ C–H bonds are more acidic than $\ce{sp^2}$ or $\ce{sp^3}$ is that the $\ce{sp}$ orbital has more s-character (50%), which holds the electrons closer to the nucleus and stabilizes the resulting anion.

Once formed, the acetylide anion is an excellent nucleophile. It attacks the electrophilic carbon of an alkyl halide in an $\ce{S_N2}$ reaction, displacing the halide leaving group. This creates a new $\ce{C(sp)-C(sp^3)}$ single bond and produces a more substituted internal alkyne, with the triple bond now positioned in the interior of the carbon chain.

Suitable halides for acetylide alkylation

Because this reaction proceeds through an $\ce{S_N2}$ mechanism, the structure of the alkyl halide matters a lot. Steric hindrance at the electrophilic carbon controls whether substitution or elimination wins out.

• Primary alkyl halides are the best substrates. The electrophilic carbon is minimally hindered, so backside attack by the acetylide proceeds smoothly. Among primary halides, reactivity follows the trend $\ce{RI > RBr > RCl}$, reflecting how easily each halide departs as a leaving group.
• Secondary alkyl halides react more slowly and give lower yields. The two alkyl groups flanking the electrophilic carbon partially block the backside attack required for $\ce{S_N2}$.
• Tertiary alkyl halides don't work. Three bulky groups completely block backside attack, shutting down $\ce{S_N2}$. Instead, the acetylide acts as a strong base, abstracting a $\beta$-hydrogen and causing $\ce{E2}$ elimination to form an alkene. This is a common pitfall on exams.
• Alkyl fluorides are also poor substrates despite being primary, because the C–F bond is very strong and fluoride is a poor leaving group.

Multi-step synthesis of internal alkynes

A typical two-step sequence for building an internal alkyne looks like this:

1. Deprotonate the terminal alkyne with a strong base to form the acetylide anion.

   • Example: Treat 1-hexyne with $\ce{NaNH2}$ to form sodium hex-1-yn-1-ide.

2. Alkylate the acetylide anion with a primary alkyl halide to form the new internal alkyne.

   • Example: React sodium hex-1-yn-1-ide with 1-bromobutane to form dec-5-yne (a symmetric 10-carbon internal alkyne).

When planning a synthesis, think about where to "cut" the target molecule at the triple bond. Each fragment tells you which terminal alkyne and which alkyl halide you need. If the target is dec-5-yne, you can disconnect at the triple bond to get a 6-carbon acetylide (from 1-hexyne) and a 4-carbon primary bromide (1-bromobutane).

• Alternative route using an alkynyl halide coupling:
  1. Halogenate a terminal alkyne to form an alkynyl halide. For example, treat 1-hexyne with $\ce{Br2}$ to form 1-bromohex-1-yne.
  2. React the alkynyl halide with a second acetylide anion. For example, combine 1-bromohex-1-yne with lithium ethynylide (formed from acetylene and $\ce{n-BuLi}$) to form oct-4-yne.

This alternative approach is less common in introductory courses but shows that you can think about C–C bond formation from either direction: the acetylide as nucleophile attacking an alkyl halide, or a different acetylide attacking an alkynyl halide as the electrophile.