Expanding the Repertoire of Large Scaffolds with and Macrocyclic Metacyclophanes.

Understanding how changes in structure translate to changes in molecular shape is key to catalyst optimization and molecular design in medicinal chemistry and materials. One key contributor to the molecular shape is the relative orientation of substituents on a scaffold. Macrocyclic metacyclophanes display their two arenes in a parallel or antiparallel fashion, resulting in or conformations that lead to disparate relative orientations of the aryl substituents. This work reports the synthesis of new 14- and 16-membered metacyclophanes and the elucidation of their / preferences by H NMR and computational conformational analysis. Most metacyclophanes studied herein display a strong or preference and, thus, have well-defined substituent orientations. We propose that / conformational preferences arise from the minimization of torsional strain along the backbone of the macrocycle, which leads to the prediction that metacyclophanes with remote aryl substituents will adopt the same conformation as their unsubstituted counterparts. Exit vector analysis also reveals that -metacyclophanes project their substituents into regions in three-dimensional space that are not accessed by other common large scaffolds, e.g., [2.2]paracyclophanes and ferrocenes. This work also demonstrates how ring size and functional groups, two parameters commonly optimized in macrocycle design, can be used to tune molecular shape.