Driving tert-butyl axial: the surprising cyclopropyl effect

Abstract

The presence of a small spirocyclic ring at an adjacent position alters the conformational preference for equatorial substitution in six-membered rings. DFT calculations and low-temperature ¹H NMR experiments demonstrate that alkyl groups larger than methyl possess negative A-values when geminal to a spirocyclopropane, with larger groups such as isopropyl and tert-butyl being exclusively axial at -78 °C. Similar effects are found for heteroatoms, including halogens, and for a range of other electron-withdrawing substituents. Similar effects are observed for other strained rings (epoxide, cyclobutane, oxetane) and the concepts extend to acyclic models as well as heterocycles such as piperidines and piperazines. The origin of the effect is traced to an increase in torsional strain in combination with hyperconjugative effects in the case of electron-poor groups.

Fig. 1. Conformational elements in cyclohexanes and examples of cyclopropane-containing relevant molecules.

Fig. 2. Preference for axial orientation in a Cope-like transition state.

Scheme 1. Synthesis of alkyl-susbstituted spirocyclopropanes.

Fig. 3. Conformations in acyclic systems.

Fig. 4. Conformational control in 2-spirocyclopropyl piperidines. (A) Calculated piperidine A-values (B) X-ray crystal structure of 3·HCl.

Scheme 2. (A) Synthesis and conformation of spirocyclopropylpiperazines (B) SCXRD of 4 (C) SCXRD of 6·(TsOH)₂·H₂O (tosylates and water have been removed for clarity – see ESI for full structure).

Fig. 5. Increased steric strain adjacent to cyclopropane. (A) NBO-STERIC calculations suggest a reduced difference between axial and equatorial epimers in the presence of a cyclopropane. (B) Modeling the effect of specific torsion angles using butane. NBO-STERIC energies were calculated fixing butane at angles found in the dimethyl and spirocyclopropyl systems. The sum of steric interactions are approximately 2 kcal mol⁻¹ higher in the equatorial isomer with cyclopropyl substitution compared to dimethyl whereas in the axial isomer the cyclopropane interactions are 0.81 kcal mol⁻¹ less.

Fig. 6. NBO orbital overlap of cyclopropane C–C σ-bond with axial C–F σ*, calculated at the M06-2X/6-311++G(2d,2p) level.