Acetylide anions are powerful tools for building carbon chains. These negatively charged molecules, formed by removing hydrogen from terminal alkynes, readily attack alkyl halides. The result? Longer, more complex alkynes with the triple bond nestled inside the molecule.

Not all halides are created equal in this reaction. Primary halides work best, while secondary ones are slower. Tertiary halides? Forget about it - they'd rather form alkenes. This selectivity makes acetylide alkylation a go-to method for precisely crafting internal alkynes in organic synthesis.

Alkylation of Acetylide Anions

Acetylide anions with alkyl halides

• Acetylide anions formed by deprotonating terminal alkynes using strong bases (sodium amide $\ce{NaNH2}$, n-butyllithium $\ce{n-BuLi}$)
  • Base removes terminal hydrogen creating resonance-stabilized carbanion with negative charge on $\ce{sp}$-hybridized carbon
  • The pKa of terminal alkynes is typically around 25, making them relatively acidic
• Acetylide anions are excellent nucleophiles due to high energy $\ce{sp}$ orbital and react readily with electrophilic alkyl halides
  • Nucleophilic acetylide anion attacks electrophilic carbon bonded to halogen displacing halide leaving group in $\ce{S_N2}$ reaction (nucleophilic substitution)
  • Alkyl group from alkyl halide becomes bonded to $\ce{sp}$-hybridized carbon forming new carbon-carbon $\ce{sp-sp^3}$ single bond (carbon-carbon bond formation)
• Produces more substituted internal alkyne with triple bond shifted to interior of carbon chain

Suitable halides for acetylide alkylation

• Primary alkyl halides are most suitable electrophiles undergoing $\ce{S_N2}$ reaction readily due to low steric hindrance around electrophilic carbon
  • Reactivity follows order $\ce{RI > RBr > RCl}$ based on leaving group ability of halide
• Secondary alkyl halides react more slowly with lower yields due to increased steric hindrance from larger alkyl groups blocking backside attack by acetylide nucleophile
• Tertiary alkyl halides are generally unreactive towards $\ce{S_N2}$ and instead undergo $\ce{E2}$ elimination to form alkenes
  • Bulky alkyl groups completely block backside preventing $\ce{S_N2}$
  • Strong base deprotonates $\ce{β}$-hydrogen leading to elimination
• Alkyl fluorides are poor substrates due to strong carbon-fluorine bond and poor leaving group ability of fluoride

Multi-step synthesis of internal alkynes

1. Deprotonation of terminal alkyne using strong base to form acetylide anion

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

2. Alkylation of acetylide anion with suitable primary alkyl halide to form new internal alkyne

   • React sodium hex-1-yn-1-ide with 1-bromobutane to form dec-5-yne

• Alternative route:
  1. Halogenation of terminal alkyne to form alkynyl halide
     • Treat 1-hexyne with $\ce{Br2}$ to form 1-bromohex-1-yne
  2. Coupling of alkynyl halide with second acetylide anion
     • React 1-bromohex-1-yne with lithium ethynylide (from acetylene and $\ce{n-BuLi}$) to form oct-4-yne