ABSTRACT
The ability to design catalysis largely depends on our understanding of the electrostatic effect of the surrounding on the bonds participating in the reaction. Here, we used a simplistic model of point charges (PCs) to determine a set of rules guiding how to construct PC-bond arrangement that can strengthen or weaken different chemical bonds. Using valence bond theory to calculate the in situ bond energies, we show that the effect of the PC mainly depends on the bond's dipole moment irrespective of its type (being covalent or charge shift). That is, polar bonds are getting stronger or weaker depending on the sign and location of the PC, whereas non- or weakly polar bonds become stronger or weaker depending only on the location of the PC and to a smaller extent compared with polar bonds. We also show that for polar bonds, the maximal bond strengthening and weakening effect can be achieved when the PC is placed along the bond axis, as close as possible to the more and less polarizable atom/fragment, respectively. Finally, due to the stabilizing effects of polarizability, we show that, overall, it is easier to cause bond strengthening compared with bond weakening. Particularly, for polar bonds, bond strengthening is larger than bond weakening obtained by an oppositely signed PC. These rules should be useful in the future design of catalysis in, e.g., enzyme active sites.
Subject(s)
Catalysis , Static ElectricityABSTRACT
A new family of titanium(IV) complexes based on [ONON] diaminobis(phenolato) ligands with Me, Br, Cl, and F ortho substitutions was synthesized and characterized. X-ray structures of three derivatives revealed homoleptic L2Ti-type compounds that exhibit an octahedral geometry without binding of the dangling amine unit. DFT calculations demonstrated that the preference of an L2Ti complex is not driven by solvent or ligand substitutions but rather by entropic effects. Except for the fluorinated derivative that was hydrolyzed immediately following water addition at room temperature and had the lowest biological activity of the series tested, all other complexes showed cytotoxic activity comparable to or higher than (up to 10-fold) that of cisplatin toward human ovarian A2780 and colon HT-29 cancer cell lines (IC50 values: 0.6-13 µM after incubation for 72 h). Activity was generally higher (up to 10-fold) toward the more sensitive ovarian line and similar for all active complexes, whereas differences were recorded toward the colon line that are attributed to bioavailability variations among the complexes analyzed. Particularly high hydrolytic stability was recorded for the brominated derivative with a t1/2 of 17 ± 1 days for ligand hydrolysis in 10% D2O at room temperature, relative to t1/2 of 56 ± 5 and 22 ± 6 h measured for the chlorinated and methylated derivatives, respectively. Altogether this series of compounds represent a promising family of anticancer agents, with the chlorinated derivative showing the best combination of stability, cytotoxicity, and bioavailability.
