A computational approach to tuning the photochemistry of platinum(IV) anticancer agents.

Diazido Pt(IV) complexes are inert stable prodrugs that can be photoactivated to produce Pt(II) species with promising anticancer activity. Our studies of the photochemistry of Pt(IV) complexes, [Pt(X)(2) (Y)(2) (Z)(2) ](0/-1) (X=N-ligands (NH(3) , pyridine, etc.)/S(CH(3) )(2) /H(-) , Y=(pseudo)halogen (N(3) (-) , I(-) ), Z=OR(-) , R=H, Ac) by time-dependent density functional theory (TDDFT) show close agreement with spectroscopic data. Broad exploration of cis/trans geometries, trans influences, the nature of the OR(-) and (pseudo)halogen ligands, electron-withdrawing/donating/delocalising substituents on the N-ligands, and intramolecular H bonds shows that: 1) the design of platinum(IV) complexes with intense bands shifted towards longer wavelengths (from 289 to ∼330 nm) can be achieved by introducing intramolecular H bonds involving the OH ligands and 2-hydroxyquinoline or by iodido ligands; 2) mesomeric electron-withdrawing substituents on pyridine result in low-energy absorption with significant intensity in the visible region; and 3) the distinct makeup of the molecular orbitals involved in the electronic transitions for cis/trans-{Pt(N(3) )(2) } isomers results in different photoproducts. In general, the comparison of the optimised geometries shows that Pt(IV) complexes with longer PtL bonds are more likely to undergo photoreduction with longer-wavelength light. The novel complex trans,trans,trans-[Pt(N(3) )(2) (OH)(2) (NH(3) )(4-nitropyridine)] with predicted absorption in the visible region has been synthesised. The experimental UV/Vis spectrum in aqueous solution correlates well with the intense band in the computed spectrum, whereas the overlay in the low-energy region can be improved by a solvent model. This combined computational and experimental study shows that TDDFT can be used to tune the coordination environment for optimising photoactive Pt(IV) compounds as anticancer agents.

An in silico design tool for Fe(II) spin crossover and light-induced excited spin state-trapped complexes.

The discovery of new coordination complexes that can support spin crossover (SCO) or light-induced excited spin state trapping (LIESST) could be radically improved by better computational tools. While methods such as density functional theory (DFT) are capable of high accuracy, they are too slow for molecular discovery, where millions of individual calculations may be required. In contrast, empirical ligand-field molecular mechanics (LFMM) captures the d-electron effects implicit in DFT and thus can be as accurate, but LFMM is up to 4 orders of magnitude faster. We demonstrate for simple Fe(II) am(m)ines how LFMM can be used to redesign "old" systems to generate novel, potential SCO and LIESST complexes.

Ligand field torque: a pi-type electronic driving force for determining ligand rotational preferences.

Transition metal complexes with triply-degenerate T ground states are formally Jahn-Teller active but do not usually display the significant bond length distortions familiar from their E ground state counterparts like d(9) Cu(II). The electronic 'asymmetry' for T-state systems lies in the d(pi) orbitals, which interact with the ligands relatively weakly compared to the stronger sigma-type interactions for E-state systems. However, in combination with asymmetric M-L pi bonding, T-type systems have an additional mechanism for relieving the electronic strain. Density functional theory, ligand field theory and ligand field molecular mechanics calculations are used to show how rotations around the M-L bonds can affect their pi-pi (d(pi)-L(pi)) interactions and lead to significant energy lowering. For example, d(6) [Fe(OH(2))(6)](2+), which has a (5)T(g) state in cubic T(h) symmetry, 'distorts' to an S(6) structure 4.4 kcal mol(-1) lower in energy (by DFT) but with six equal Fe-O distances via Fe-O rotations of approximately 20 degrees and thus masquerades as an apparently regular geometry. Using model systems, we show that this effect is not restricted to formally Jahn-Teller active complexes. The combination of asymmetric pi bonding and asymmetric d(pi) orbital occupations can generate an M-L 'torque' worth up to 6 kcal mol(-1) per bond which can 'lock' the ligand in a particular orientation relative to the partially-occupied d orbital(s). The effect is particularly marked for imidazole, the donor group of histidine, which, in a model low-spin d(5) Fe(III) system, shows almost no orientational preference in its neutral form but a very strong (approximately 6 kcal mol(-1)) orientational preference in its deprotonated form.

Capturing the Trans Influence in Low-Spin d(8) Square-Planar Platinum(II) Systems using Molecular Mechanics.

Molecular modeling of coordination complexes continues to present challenges for force field methods. Implicit or explicit treatment of the significant d electron effects is mandatory. Ligand field molecular mechanics is designed for coordination complexes by explicitly including the ligand field stabilization energy (LFSE) and it is applied here to model the trans influence in tetracoordinate Pt(II) complexes of general formulas PtX4, PtX3Y, cis-PtX2Y2, and trans-PtX2Y2, where X and Y are OH2, H(-), Cl(-), Br(-), PR3, SH2, NR3, and pyridine. Parameters have been developed within the Merck molecular force field using DFT structures and energies as reference data. Both geometric changes and relative energies are generally well-reproduced although PH3 and H(-) complexes show deviations. However, for phosphine complexes, replacing PH3 with PMe3 resolves all bar one of these. The LFSE associated with the low-spin d(8) configuration ensures planar coordination and provides an electronic connection between all the ligands, thus enabling a correct description of the trans influence. The parameters developed for NR3 and PR3 with R = H work well for R = Me and Et and, in agreement with experimental and/or DFT structures, display either a tetrahedral distortion or even ligand dissociation.

Electronic structure of bispidine iron(IV) oxo complexes.

The electronic structure, based on DFT calculations, of a range of FeIV=O complexes with two tetra- (L1 and L2) and two isomeric pentadentate bispidine ligands (L3 and L4) is discussed with special emphasis on the relative stability of the two possible spin states (S = 1, triplet, intermediate-spin, and S = 2, quintet, high-spin; bispidines are very rigid diazaadamantane-derived 3,7-diazabicyclo[3.3.1]nonane ligands with two tertiary amine and two or three pyridine donors, leading to cis-octahedral [(X)(L)FeIV=O]2+ complexes, where X = NCCH3, OH2, OH-, and pyridine, and where X = pyridine is tethered to the bispidine backbone in L3, L4). The two main structural effects are a strong trans influence, exerted by the oxo group in both the triplet and the quintet spin states, and a Jahn-Teller-type distortion in the plane perpendicular to the oxo group in the quintet state. Due to the ligand architecture the two sites for substrate coordination in complexes with the tetradentate ligands L1 and L2 are electronically very different, and with the pentadentate ligands L3 and L4, a single isomer is enforced in each case. Because of the rigidity of the bispidine ligands and the orientation of the "Jahn-Teller axis", which is controlled by the sixth donor X, the Jahn-Teller-type distortion in the high-spin state of the two isomers is quite different. It is shown how this can be used as a design principle to tune the relative stability of the two spin states.