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 sol id state. MMX calculations suggest that the global energy minimum structure s are bent in the gas phase, probably owing to edge-to-face intramolecular attractive interaction between the electron rich and the electron poor term inal aryl groups. These conformations were confirmed in solution using 2D N OESY NMR. In the solid state, 1 and 2 exist in the staggered, linear confor mation, stacked head-to-tail, with the plane of the nitro group being tilte d 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 we re treated with trifluoromethanesulfonic acid to generate the nitrenium ion s, which underwent intramolecular ring-closure to give the corresponding 17 - and 19-membered ring thiamacrocycles in modest yields. These results supp ort the suggestion that MMX calculations on appropriate model compounds may be useful in predicting which precursors will lead to macrocycles and whic h will not.