Figure 7. Geometries of the stationary points in the
intramolecular reaction of intermediate med1 to form 3a .
For path 1, we assumed that the H+ in solution is not
involved in the cyclization process. Although various configurations
were tested, the transition state of this process was not found using
either the ts, qst2, or qst3 method. The C(8)–O(14) bond length was
scanned flexibly. The structural changes and energy curve during the
scan are shown in Figures 8 and 9, respectively. The scan shows that as
C(8) and O(14) become far away from
each other, the energy of the system continuously increases without
reaching the highest point in energy. When C(8) and O(14) are not
bonded, the C(8)–N(7) bond is broken and a very unstable 8-membered
ring system is formed. At the same time, after the structure of
intermediate med1-1 is optimized, the C(8)–O(14) bond breaks and cannot
form a stable five-membered ring, which proves that med1-1 is unstable
under these conditions. Therefore, path 1 cannot occur, and it was
hypothesized that H+ participates in the formation of
the five-membered ring.