Synthesis, crystal structure, and resolution of [10](1,6)pyrenophane: an inherently chiral [N]cyclophane.

A synthetic approach to a set of three inherently chiral [n]cyclophanes, npyrenophanes (29a-c, n = 8-10) was investigated. Progress toward 29a was thwarted by the failure of the key dithiacyclophane-forming reaction. For the next higher homologue, the synthesis was completed, but the desired 9pyrenophane (29b) could only be partially separated from an isomeric pyrenophane, 9pyrenophane (28b), and an unidentified byproduct. Work aimed at the synthesis of the next higher homologue resulted in the isolation of a 7:4 mixture of 10pyrenophane (28c) and 10pyrenophane (29c), which could not be separated by column chromatography or crystallization. However, single-crystal X-ray structures of 28c and 29c were obtained after manual separation of two crystals with different morphologies from the same batch of crystals obtained from the 7:4 mixture of 28c and 29c. The pyrene system of 29c was found to have a gentle end-to-end bend as well as a significant longitudinal twist. Short intermolecular C(sp(3))-H···π contacts (2.64 to 2.76 Å) between H-atoms on the bridge and the centroids of three of the four six-membered rings of the pyrene system of a neighboring pyrenophane of like chirality give rise to the formation of single enantiomer columns. From a DNMR study of the mixture of 28c and 29c, the bridge in 10pyrenophane (28c) was found to undergo a conformational flip from one side of the pyrene system to the other with ΔG(‡) = 14.9 ± 0.2 kcal/mol. A two-stage preparative HPLC protocol was subsequently developed for the separation of 28c and 29c (Chiralpak AD-H column) and then the enantiomers of 29c (Chiralcel OJ-H column). This enabled the measurement of their optical rotations and CD spectra.