NivaarExam PrepOfficial exam papers ↗

04-BS-12 · December 2016

Question 7 of 13: Multi-Step Synthesis from Acetylene (≤2-Carbon Building Blocks)

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 7: Multi-Step Synthesis from Acetylene (≤2-Carbon Building Blocks)

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. All four targets share the identical six-carbon, one-alkene skeleton (only the double-bond geometry and the terminal functional group differ), so the efficient strategy is to build one common alkynol from acetylene using two separate ≤2-carbon electrophiles, then branch at the very end: partial/dissolving-metal reduction sets the alkene geometry (a vs. b), and (b) is itself the common precursor for the halide (c) and the aldehyde (d).

  1. Build the C6 skeleton: two sequential acetylide alkylations on acetylene. Deprotonate acetylene with 1 equiv. NaNH2, then alkylate with ethylene oxide (a 2-carbon electrophile) to install a –CH2CH2OH arm.
    acetylene
    ethylene oxide
    (1) NaNH2; (2) ethylene oxide; (3) H3O+
    →
    3-butyn-1-ol
    Deprotonate again with excess NaNH2 (2 equiv. total are needed — one consumed by the newly formed O–H, one to generate the terminal acetylide) and alkylate the acetylide carbon with ethyl bromide (the second 2-carbon electrophile):
    (1) 2 eq. NaNH2; (2) CH3CH2Br; (3) H3O+
    →
    hex-3-yn-1-ol (common intermediate)
  2. (a) Lindlar (syn) hydrogenation → cis alkene. H2/Lindlar catalyst (Pd/CaCO3, quinoline-poisoned) adds both hydrogens to the same face of the triple bond, giving the Z-alkene directly.
    hex-3-yn-1-ol
    H2, Lindlar catalyst
    →
    (Z)-hex-3-en-1-ol
  3. (b) Dissolving-metal (Na/NH3) reduction → trans alkene. Sodium in liquid ammonia reduces internal alkynes via a radical-anion/vinyl-radical pathway that equilibrates to the thermodynamically more stable trans-vinyl radical before the second electron transfer, delivering the E-alkene.
    hex-3-yn-1-ol
    Na, NH3(l)
    →
    (E)-hex-3-en-1-ol
  4. (c) PBr3 on the (E)-alcohol — alcohol→bromide, alkene untouched. PBr3 converts the primary alcohol to the primary bromide by an SN2-type mechanism at carbon far from the double bond; the alkene geometry is not involved in this step and is preserved.
    (E)-hex-3-en-1-ol
    PBr3
    →
    (E)-1-bromohex-3-ene
  5. (d) PCC on the (E)-alcohol — mild oxidation stops at the aldehyde. Pyridinium chlorochromate (PCC) in CH2Cl2 oxidises a primary alcohol only as far as the aldehyde (no aqueous/acidic conditions to carry it on to the carboxylic acid) and does not touch the internal alkene.
    (E)-hex-3-en-1-ol
    PCC, CH2Cl2
    →
    (E)-hex-3-enal