Figure 16. The chemical structure of the ligand-AB3dendritic-prodrug conjugate comprising seven components corresponding to four function types.
We performed geometry optimization at the PM6 level, using the PCM of solvation, in the Gaussian 09 package. We then elongated the CO–N(H) bond between components two and three and performed TS optimization using QST3 with the PCM at the same level as the optimization step. Atoms except for those related to the CO–N(H) of components two and three were frozen during transitions-state optimization for simplification because a more elaborate mechanism is beyond the scope of this study. Vibrational-mode analysis indicated a unique imaginary frequency of −344.76 cm−1 related to bond stretching along the direction of targeted CO–N(H) bond. IRC calculations to confirm the TS structure using a 0.2-Bohr step size showed that the structure (Figure 17) demonstrated a final point of forward direction (R’) located at a C–N(H) bond distance of 1.68 Å, with a PM6 total energy of −0.575206 Hartree. To identify the remaining structural and energetic differences between the R’ and the true-minimum R, we optimized the structure with all atoms relaxed in order to reach the ground state. The re-optimization of R’ resulted in a fully optimized structure with a total energy of −0.676 Hartree and a CO–N(H) bond distance of 1.39 Å, which was highly similar to the reactant and confirmed the correctness of desired TS.