Question 8 of 13: Halohydrin → Epoxide Ring Closure — Conformational Control

Question 8: Halohydrin → Epoxide Ring Closure — Conformational Control

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.

Ring closure to an epoxide is an intramolecular Williamson ether synthesis: the alkoxide oxygen must attack the C–Cl carbon from the backside (S_N2), which is only geometrically possible when the O and Cl are trans-diaxial (anti-periplanar) in the reacting conformation. The bulky tert-butyl group is far too large to ever be axial, so it locks each molecule into whichever single chair keeps it equatorial — and that lock is what decides whether the O/Cl pair can reach the diaxial geometry needed to react.

1. (a) Fast. Here Cl is cis to the tert-butyl group (a 1,4-like relationship, so cis places one substituent axial/one equatorial, while OH sits 1,3 to the tert-butyl group in a trans relationship, which also forces one axial/one equatorial). Working through both constraints together, the chair that keeps the bulky group equatorial already places both O and Cl axial — the molecule's single accessible (low-energy) conformation is simultaneously its reactive conformation, so ring closure is fast. (Confirmed computationally below: the global-minimum MMFF conformer of this stereoisomer has both C–O and C–Cl bonds axial.)
2. (b) Slow / intermediate. This diastereomer instead places OH cis to the tert-butyl group; working through the same relationships, the low-energy (tert-butyl equatorial) chair now has all three substituents equatorial — including O and Cl, which is the wrong geometry for ring closure. The only way to get O and Cl diaxial is to flip the entire ring, which simultaneously forces the bulky tert-butyl group axial — a very high-energy conformation that is populated only rarely at equilibrium. The reaction can still occur (it passes through that rare, reactive conformer occasionally), just far more slowly than (a), whose reactive geometry is already the dominant conformation.
3. (c) No reaction. This isomer has Cl cis to OH — a cis-1,2 relationship. For any 1,2-disubstituted cyclohexane, cis substituents are always one axial + one equatorial, in either chair; ring-flipping just exchanges which one is which, but they can never be simultaneously axial. Since trans-diaxial O/Cl is geometrically impossible for this diastereomer regardless of which chair it adopts, it cannot achieve the anti-periplanar alignment needed for backside attack at all — it does not form the epoxide by this mechanism, no matter how long the reaction is run.