Stereoselective formation of seven-coordinate titanium(IV) monomer and dimer complexes of ethylenebis(o-hydroxyphenyl)glycine

Reactions between the antitumor agent titanocene dichloride (Cp2TiCl2) and the hexadentate ligand N,N‘-ethylenebis(o-hydroxyphenylglycine) (H4ehpg) have been investigated in aqueous solution and the solid state. The racemic ligands give crystals of the monomer [Ti(ehpg)(H2O)]·(11/3)H2O (1), while the meso ligand gives the oxo-bridged dimer [{Ti(Hehpg)(H2O)}2O]·13H2O (2). Complex 1 crystallizes in the monoclinic space group C2/c with a = 24.149(4) Å, b = 14.143(3) Å, c = 19.487(3) Å, β = 105.371(13)°, V = 6417.7(19) Å3, Z = 12, and R(F) = 0.0499 for 4428 independent reflections having I > 2σ(I), and contains seven-coordinate pentagonal-bipyramidal TiIV with two axial phenolate ligands (Ti−O, 1.869(2) Å). The pentagonal plane contains the two N-atoms at 2.210(2) Å, two carboxylate O-atoms at 2.061(2) Å, and a water molecule (Ti−OH2, 2.091(3) Å). Complex 2 crystallizes as an oxygen-bridged dimer in the triclinic space group P-1 with a = 12.521(6) Å, b = 14.085(7) Å, c = 16.635(8) Å, α = 80.93(2)°, β = 69.23(2)°, γ = 64.33(2)°, V = 2472(2) Å3, Z = 4, and R(F) = 0.0580 for 5956 independent reflections having I > 2σ(I). Each seven-coordinate, pentagonal-bipyramidal TiIV has a bridging oxide and a phenolate as axial ligands. The pentagonal plane donors are H2O, two carboxylate O-atoms, and two NH groups, which form H-bonds to O-atoms both in the same half-molecule (O···N, 2.93−3.13 Å) and in the other half-molecule (O···N, 2.73−2.75 Å); the second phenoxyl group of each Hehpg ligand is protonated and not coordinated to TiIV, but H-bonds to a nearby amine proton (O···N, 2.73−2.75 Å) from the same ligand and to a nearby H2O (O···O, 2.68 Å). In contrast to all previously reported crystalline metal−EHPG complexes containing racemic ligands, in which the N(S,S)C(R,R) or N(R,R)C(S,S) form is present, complex 1 unexpectedly contains the N(S,S)C(S,S) and N(R,R)C(R,R) forms. This is attributed to the presence of ring strain in seven-coordinate TiIV complexes. Moreover, the rac ligands selectively form crystals of monomeric 1, while the meso ligand selectively forms crystals of the dimer 2 (N(R,R)C(R,S) or N(S,S)C(S,R)). Complexes 1 and 2 exhibit phenolate-to-TiIV charge-transfer bands near 387 nm, and 2D NMR studies indicate that the structures of 1 and 2 in solution are similar to those in the solid state. Complex 1 is stable over the pH range 1.0−7.0, while 2 is stable only between pH 2.5 and pH 5.5. Cp2TiCl2 reacts with EHPG at pH* 7.0 to give complex 1 with a t1/2 of ca. 50 min (298 K), but complex 2 was not formed at this pH* value. At pH* 3.7, the reaction is very slow:  1 forms with a half-life of ca. 2.5 d, and 2 after ca. 1 week at ambient temperature. The relevance of these data to the possible role of serum transferrin as a mediator for the delivery of TiIV to tumor cells is discussed.