The First In-Ketocyclophane

Over the years, we have prepared many cyclophanes with inwardly-directed functional groups, but in each case the in-group has had three points of attachment (three linking arms) to the base of the cyclophane. This restricts the ability of the functional group to bend away from the base. The synthesis of an in-ketone presents a special challenge because carbonyl groups have only two points of attachment, and in most structures can easily tilt away from the basal benzene ring. However, computational studies suggested that benzophenone-capped cyclophanes with highly substituted linking arms would prefer to adopt in-conformations. The X-ray structure of the first such molecule is shown below. In this bis-sulfone, the ketone points directly at the aromatic ring, but in its bis-thioether precursor, which has "floppier" linking arms, the ketone is able to bend away. For a brief communication describing both computational and experimental studies of the in-ketocyclophane, see Qin, Q., J. T. Mague, and R. A. Pascal, Jr., Org. Lett. 2010, 12, 928-930.