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04-BS-12 · December 2016

Question 6 of 13: Retrosynthesis of Internal Alkynes via Acetylide Alkylation

Nivaar worked solution (AI-drafted; not reviewed by a licensed engineer)

Notes on this paper

National Exam 04-BS-12, Organic Chemistry — December 2016. 3 hours, closed-book examination (no non-communicating calculator restriction beyond the standard aid sheet, 8.5×11", hand-written both sides). Ten questions constitute a complete exam paper (only the first 10 questions as they appear in the answer book are marked, each of equal value) — the source paper in fact prints thirteen questions; all thirteen are answered in full below.

Reference texts: McMurry, Organic Chemistry, 9th ed. (acid/base theory of drugs, SN1/SN2 stereochemistry, carbocation rearrangements, alkyne synthesis via acetylide alkylation, IR/NMR structure elucidation, electrophilic aromatic substitution and synthesis design, amino-acid pKa); Clayden, Organic Chemistry, 2nd ed. (amide resonance and β-lactam reactivity, radical vs. ionic HBr addition mechanisms); a standard biomaterials reference for the poly(ester amide) drug-delivery polymer chemistry of Question 13 (Katsarava-type AABB poly(ester amide)s built from diacids, diols, and protected diamino acids).

Question 6: Retrosynthesis of Internal Alkynes via Acetylide Alkylation

Question text not reproduced: the examination questions are © Engineers and Geoscientists BC. Open the official past paper (linked at the top of this page) to read the question, then follow the worked solution below.

Approach. An internal alkyne is disconnected at the C(sp)–C(sp3) bond formed by alkylating a metal acetylide (R–C≡C:−) with a primary alkyl halide (SN2). Because the acetylide's own SN2 alkylation step requires an unhindered, primary electrophile, the disconnection must always put the alkyl-halide fragment on whichever side of the target's internal alkyne is not attached to a bulky/hindered carbon — alkylating with a secondary or tertiary halide is not viable (competing E2 dominates), so that side must instead already be part of the acetylide.

  1. (a) One alkyne terminus is a plain terminal C–H — that side is unreacted acetylene itself. The target keeps a terminal alkyne C–H, so only a single alkylation occurred, on acetylene's other carbon.
    target (a)
    Retrosynthesis: disconnect the C–C bond to the isohexyl chain.
    1-chloro-3-methylbutane
    + HC≡C:− Na+, SN2
    →
    target (a)
    Acetylide = sodium acetylide (HC≡C:− Na+, from HC≡CH + NaNH2); alkyl halide = 1-halo-3-methylbutane (isopentyl halide, primary).
  2. (b) One side of the alkyne is a plain CH3; the other is a fully substituted (no-H) carbon. A quaternary-adjacent carbon such as –C(CH3)2CH2CH3 could never itself be delivered by an SN2 alkyl halide (it would have to be a neopentyl/tertiary-type electrophile, hopeless for SN2) — so that whole branched fragment must already be on the acetylide, and only the lone terminal CH3 was added by alkylation.
    target (b)
    3,3-dimethylpent-1-yne (as its acetylide)
    + CH3–X, SN2
    →
    target (b)
    Acetylide = the anion of 3,3-dimethylpent-1-yne, −:C≡C–C(CH3)2CH2CH3; alkyl halide = CH3X (methyl halide, e.g. CH3I).
  3. (c) One side is a secondary (ring) carbon, the other a primary propyl chain — alkylate on the unhindered propyl side. A cyclohexyl halide is secondary and would be a poor, elimination-prone SN2 electrophile, so the ring must already be part of the acetylide; the straight-chain propyl group is what gets added.
    target (c)
    ethynylcyclohexane (as its acetylide)
    + CH3CH2CH2–X, SN2
    →
    target (c)
    Acetylide = cyclohexylacetylide (from ethynylcyclohexane + NaNH2); alkyl halide = 1-halopropane (e.g. 1-bromopropane).