Mechanistic study of hemicucurbit[6]uril formation by step-growth oligomerization and end-to-end cyclization

The formation of hemicucurbit[6]uril (hCB[6]) from ethyleneurea with formaldehyde in acidic aqueous solution was explored using density functional methods and the implicit solvation model in water. The oligomerization and cyclization barriers were approximately half lower than that of the iminium formation. Thus, the initial iminium formation is the rate-determining step, and the formation of hCB[6] is kinetically and thermodynamically favored in acidic aqueous solution. In particular, the ‘alternate’ conformation of hCB[6] is enthalpically and entropically preferred over the ‘cone’ conformation, which is consistent with the crystal structure of hCB[6].