Synthesis of Thiamacrocycles and Conformational Studies on Their Precursors

1-(4-Nitrophenyl)-7-phenylthioheptane (1) and -9-phenylthiononane (2) have been synthesized and their conformations studied in solution and in the solid state. MMX calculations suggest that the global energy minimum structures are bent in the gas phase, probably owing to edge-to-face intramolecular attractive interaction between the electron rich and the electron poor terminal aryl groups. These conformations were confirmed in solution using 2D NOESY NMR. In the solid state, 1 and 2 exist in the staggered, linear conformation, stacked head-to-tail, with the plane of the nitro group being tilted above the plane of the benzene ring. It appears that the crystal lattice forces overcome the weak edge-to-face intramolecular aromatic interactions that dominate in the gas phase and in solution. The corresponding azides were treated with trifluoromethanesulfonic acid to generate the nitrenium ions, which underwent intramolecular ring-closure to give the corresponding 17- and 19-membered ring thiamacrocycles in modest yields. These results support the suggestion that MMX calculations on appropriate model compounds may be useful in predicting which precursors will lead to macrocycles and which will not.