Amphidynamic crystals of a steroidal bicyclo[2.2.2]octane rotor: a high symmetry group that rotates faster than smaller methyl and methoxy groups

Abstract

The synthesis, crystallization, single crystal X-ray structure, and solid state dynamics of molecular rotor 3 provided with a high symmetry order and relatively cylindrical bicyclo[2.2.2]octane (BCO) rotator linked to mestranol fragments were investigated in this work. By use of solid state (13)C NMR, three rotating fragments were identified within the molecule: the BCO, the C19 methoxy and the C18 methyl groups. To determine the dynamics of the BCO group in crystals of 3 by variable temperature (1)H spin-lattice relaxation (VT (1)H T1), we determined the (1)H T1 contributions from the methoxy group C19 by carrying out measurements with the methoxy-deuterated isotopologue rotor 3-d6. The contributions from the quaternary methyl group C18 were estimated by considering the differences between the VT (1)H T1 of mestranol 8 and methoxy-deuterated mestranol 8-d3. From these studies it was determined that the BCO rotator in 3 has an activation energy of only 1.15 kcal mol(-1), with a barrier for site exchange that is smaller than those of methyl (E(a) = 1.35 kcal mol(-1)) and methoxy groups (E(a) = 1.92 kcal mol(-1)), despite their smaller moments of inertia and surface areas.

Figure 1

Line diagrams of crystalline compounds with fast rotating portions in red and static fragments in blue. At 25 °C, the phenylene ring in compound 1 with a syn-steroid orientation presents two distinct dynamic processes with site exchange rates of ca. 1.5 × 10⁶ and >10⁶ s⁻¹. Ordered and disorderd sites of the bicyclo[2.2.2]octane in 2 have site exchange rates of ca. and 4.3 × 10¹¹ s⁻¹ and 7.7 × 10¹⁰ s⁻¹, respectively. A combination of components in molecular rotor 3 studied in this paper is expected to facilitate faster rotation.

Figure 2

(a) Molecular structure of the molecular rotor 3 showing the disordered bicyclo[2.2.2]octane rotator over two positions. (b) Packing arrangement of compound 3 showing a ribbon-like array found in the P4₃2₁2 space group.

Figure 3

(a) Misalignment between the crystallographic [C₂(cryst)] and bicyclo[2.2.2]octane [C₂(BCO)] two-fold symmetry axes gives rise to the two sites of the BCO fragment in 3 with the two symmetry related positions colored purple (light) and red (dark). (b) Close up of the resulting crystallographic disorder with 50:50 occupancy with the hydrogen atoms removed for clarity.

Figure 4

Comparison of the measured spin lattice relaxation rates 1/T₁ of compounds studied in this paper. In compound 3 both the BCO and MeO groups contribute with significance to the relaxation process (triangles). In crystals of methoxy-deuterated 3-d₆ the BCO group is the main responsible of the relaxation (filled squares). Similarly, the MeO group causes the relaxation in mestranol 8 (open circles) whereas the Me group is responsible for the relaxation in methoxy-deuterated mestranol 8-d₃ (solid circles).

Figure 5

(a) Components of molecular rotor 3 involved in dynamic processes. (b) Qualitative representation of the rotational potential with angular displacements between the sites of the BCO (green and purple). While the two sites are isoenergetic (50% occupancy each), each of the two barriers may have different heights, such that the measured activation energy is an average.

Scheme 1

Reagents and conditions: a) MeI or CD₃I, NaH, THF, r.t., 5 (94%), 5-d₃ (90%); b) DMSO, (COCl)₂, Et₃N, CH₂Cl₂, −78 – 0 °C; c) CBr₄, PPh₃, CH₂Cl₂, 0 °C – r.t., 95% over two steps; d) i. n-BuLi, THF, −78 – 0 °C; ii. MgBr₂·OEt₂, Et₂O, −78 °C; iii. 5 or 5-d₆, THF, CH₂Cl₂, −78 °C – r.t., 3 (46%), 3-d₆ (53%).