Robert J. Deeth

The ligand field molecular mechanics model and the stereoelectronic effects of d and s electrons

Abstract This review discusses modifications and extensions of Molecular Mechanics which are designed to model the electronic effects of the valence d and s electrons in transition metal compounds. These effects lead to severe distortions away from the ideal geometries predicted by simple VSEPR theory. The stereochemical activity of d electrons manifests in a range of structural distortions of ionic coordination complexes typified by the Jahn–Teller elongations of six-coordinate d 9 Cu 2+ species. Modelling these effects requires an additional term in the strain energy which describes the attendant ligand field stabilisation energy (LFSE). The LFSE is explicitly incorporated into the ligand field molecular mechanics (LFMM) method which has been applied to a range of complexes of Cu 2+ , Ni 2+ and Co 3+ . A single set of LFMM parameters for a given metal–ligand interaction is able to model different coordination numbers, spin states and bond lengths. The stereochemical activity of the valence metal s orbital is significant for covalent organometallic species such as WMe 6 which does not show the regular octahedral geometry expected for a formally d 0 system. The effect can be treated within Valence Bond theory by modifying the expressions for the angle bending potentials based on Paulings strength functions for sd n hybrids. There is more than one idealised bond angle for sd 3 , sd 4 and sd 5 hybrids which correlates with the irregular geometries found for hydride, alkyl and aryl compounds. The same behaviour can also be obtained within the LFMM scheme by using an extended stabilisation energy term which incorporates the s orbital contributions. The LFMM model also predicts the ligand field contribution to the activation energy for ligand exchange/substitution and can be used to calculate the structures and energies of transition states as illustrated by model calculations for the reactions of low-spin d 8 complexes.

Amide Linkage Isomerism As an Activity Switch for Organometallic Osmium and Ruthenium Anticancer Complexes

We show that the binding mode adopted by picolinamide derivatives in organometallic Os(II) and Ru(II) half-sandwich complexes can lead to contrasting cancer cell cytotoxicity. N-Phenyl picolinamide derivatives (XY) in Os(II) (1, 3-5, 7, 9) and Ru(II) (2, 6, 8, 10) complexes [(eta(6)-arene)(Os/Ru)(XY)Cl](n+), where arene = p-cymene (1-8, 10) or biphenyl (9), can act as N,N- or N,O-donors. Electron-withdrawing substituents on the phenyl ring resulted in N,N-coordination and electron-donating substituents in N,O-coordination. Dynamic interconversion between N,O and N,N configurations can occur in solution and is time- and temperature- (irreversible) as well as pH-dependent (reversible). The neutral N,N-coordinated compounds (1-5 and 9) hydrolyzed rapidly (t(1/2) <or= min), exhibited significant (32-70%) and rapid binding to guanine, but no binding to adenine. The N,N-coordinated compounds 1, 3, 4, and 9 exhibited significant activity against colon, ovarian, and cisplatin-resistant ovarian human cancer cell lines (3 >> 4 > 1 > 9). In contrast, N,O-coordinated complexes 7 and 8 hydrolyzed slowly, did not bind to guanine or adenine, and were nontoxic.

The performance of nonhybrid density functionals for calculating the structures and spin states of Fe(II) and Fe(III) complexes

The local density approximation and a range of nonhybrid gradient corrected density functionals (PW91, BLYP, PBE, revPBE, RPBE) have been assessed with respect to the prediction of geometries and spin‐state energy preferences for a range of homoleptic Fe(II)L6 and Fe(III)L6 complexes, where L = Cl−, CN−, NH3, pyridine, imidazole, H2O, OCH2 and tetrahydrofuran. While the qualitative spin‐state energies from in vacuo structure optimizations are reasonable the geometries are relatively poorly treated, especially for [FeCl6]3−/4−. Structural results for all the complexes are significantly improved by including environmental effects. The best compromise between structural and spin‐state predictive accuracy was obtained for the RPBE functional in combination with the COSMO solvation approach. This approach systematically overestimates the energetic preference for a low spin state, which is partly due to the well‐known effect of the lack of exact exchange in nonhybrid functionals and partly due to the larger solvation stabilization of low‐spin complexes that have shorter bond lengths and thus smaller molecular volumes than their high‐spin partners. Calculations on low spin [Fe(bipy)3]2+ and [Fe(phen)3]2+ and their ortho methyl substituted analogs, which are high spin at room temperature but cross over to low spin at low temperature, suggest the RPBE/COSMO combination generates low spin states which are too stable by approximately 13 kcal mol−1.

Ruthenium(II) arene anticancer complexes with redox-active diamine ligands

The synthesis and characterization of ruthenium(II) arene complexes of the general formula [(eta(6)-arene)Ru(XY)Z](+), where arene = p-cymene (p-cym), hexamethylbenzene (hmb), or biphenyl (bip), XY = o-phenylenediamine (o-pda), o-benzoquinonediimine (o-bqdi), or 4,5-dimethyl-o-phenylenediamine (dmpda), and Z = Cl, Br, or I, are reported (complexes 1-6). In addition, the X-ray crystal structures of [(eta(6)-p-cym)Ru(o-pda)Cl]PF(6) (1) and [(eta(6)-hmb)Ru(o-bqdi)Cl]PF(6) (3PF(6)) are described. The Ru-N distances in 3PF(6) are significantly shorter [2.033(4) and 2.025(4) A] compared to those in 1 [2.141(2) and 2.156(2) A]. All of the imine complexes (3-5) exhibit a characteristic broad (1)H NMR NH resonance at ca. delta 14-15. Complex 1 undergoes concomitant ligand-based oxidation and hydrolysis (38% after 24 h) in water. The oxidation also occurs in methanol. The iodido complex [(eta(6)-p-cym)Ru(o-bqdi)I]I (4) did not undergo hydrolysis, whereas the chlorido complex 3 showed relatively fast hydrolysis (t(1/2) = 7.5 min). Density functional theory calculations showed that the total bonding energy of 9-EtG in [(eta(6)-p-cym)Ru(o-pda)(9-EtG-N7)](2+) (1EtG) is 23.8 kJ/mol lower than that in [(eta(6)-p-cym)Ru(o-bqdi)(9-EtG-N7)](2+) (3EtG). The greater bonding energy is related to the contribution from strong hydrogen bonding between the NH proton of the chelating ligand and O6 of 9-EtG (1.69 A). A loss of cytotoxic activity was observed upon oxidation of the amine ligand to an imine (e.g., IC(50) = 11 microM for 1 and IC(50) > 100 microM for 3, against A2780 ovarian cancer cells). The relationship between the cytotoxic activity and the solution and solid state structures of the imine and amine complexes is discussed.

Inclusion of the ligand field contribution in a polarizable molecular mechanics: SIBFA‐LF

To account for the distortion of the coordination sphere that takes place in complexes containing open‐shell metal cations such as Cu(II), we implemented, in sum of interactions between fragments ab initio computed (SIBFA) molecular mechanics, an additional contribution to take into account the ligand field splitting of the metal d orbitals. This term, based on the angular overlap model, has been parameterized for Cu(II) coordinated to oxygen and nitrogen ligands. The comparison of the results obtained from density functional theory computations on the one hand and SIBFA or SIBFA‐LF on the other shows that SIBFA‐LF gives geometric arrangements similar to those obtained from quantum mechanical computations. Moreover, the geometric improvement takes place without downgrading the energetic agreement obtained from SIBFA. The systems considered are Cu(II) interacting with six water molecules, four ammonia or four imidazoles, and four water plus two formate anions.

Is Enantioselectivity Predictable in Asymmetric Catalysis

Seeing into the future: A range of computational methods have been applied to harmonize predicted ee values with experimental values. Novel ways of combining quantum mechanics and molecular mechanics feature prominently.

Origins of stereoselectivity in optically pure phenylethaniminopyridinetris-chelates M(NN′)3n+ (M = Mn, Fe, Co, Ni and Zn)

One-pot reactions of 2-pyridinecarboxaldehyde, chiral phenylethanamines and Fe(II) give single diastereomer fac diimine complexes at thermodynamic equilibrium so that no chiral separations are required (d.r. > 200 : 1). The origins of this stereoselectivity are partly steric and partly a result of the presence of three sets of inter-ligand parallel-offset π-stacking interactions. Mn(II), Co(II), Co(III), Ni(II) and Zn(II) give similar fac structures, alongside the imidazole analogues for Fe(II). While most of the complexes are paramagnetic, the series of molecular structures allows us to assess the influence of the π-stacking present, and there is a strong correlation between this and the M-N bond length. Fe(II) is close to optimal. For the larger Zn(II) ion, very weak π-stacking leads to poorer measured stereoselectivity (NMR) but this is improved with increased solvent polarity. The mechanism of stereoselection is further investigated via DFT calculations, chiroptical spectroscopy and the use of synthetic probes.

Reduction of Quinones by NADH Catalyzed by Organoiridium Complexes

One electron at a time: Half-sandwich organometallic cyclopentadienyl–IrIII complexes containing N,N-chelated ligands can catalyze the reduction of quinones (Q), such as vitamin K3, to semiquinones (Q.ˉ) by coenzyme NADH (see picture). DFT calculations suggest that the mechanism involves hydride transfer followed by two one-electron transfers and the unusual IrII oxidation state as a key transient intermediate.

DommiMOE: An implementation of ligand field molecular mechanics in the molecular operating environment

The ligand field molecular mechanics (LFMM) model, which incorporates the ligand field stabilization energy (LFSE) directly into the potential energy expression of molecular mechanics (MM), has been implemented in the “chemically aware” molecular operating environment (MOE) software package. The new program, christened DommiMOE, is derived from our original in‐house code that has been linked to MOE via its applications programming interface and a number of other routines written in MOEs native scientific vector language (SVL). DommiMOE automates the assignment of atom types and their associated parameters and popular force fields available in MOE such as MMFF94, AMBER, and CHARMM can be easily extended to provide a transition metal simulation capability. Some of the unique features of the LFMM are illustrated using MMFF94 and some simple [MCl4]2− and [Ni(NH3)n]2+ species. These studies also demonstrate how density functional theory calculations, especially on experimentally inaccessible systems, provide important data for designing improved LFMM parameters. DommiMOE treats Jahn–Teller distortions automatically, and can compute the relative energies of different spin states for Ni(II) complexes using a single set of LFMM parameters.

A Unified Treatment of the Relationship Between Ligand Substituents and Spin State in a Family of Iron(II) Complexes

Abstract The influence of ligands on the spin state of a metal ion is of central importance for bioinorganic chemistry, and the production of base‐metal catalysts for synthesis applications. Complexes derived from [Fe(bpp)2]2+ (bpp=2,6‐di{pyrazol‐1‐yl}pyridine) can be high‐spin, low‐spin, or spin‐crossover (SCO) active depending on the ligand substituents. Plots of the SCO midpoint temperature (T 1/2 ) in solution vs. the relevant Hammett parameter show that the low‐spin state of the complex is stabilized by electron‐withdrawing pyridyl (“X”) substituents, but also by electron‐donating pyrazolyl (“Y”) substituents. Moreover, when a subset of complexes with halogeno X or Y substituents is considered, the two sets of compounds instead show identical trends of a small reduction in T 1/2 for increasing substituent electronegativity. DFT calculations reproduce these disparate trends, which arise from competing influences of pyridyl and pyrazolyl ligand substituents on Fe‐L σ and π bonding.