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Robert J Deeth

Publications and source records attributed to Robert J Deeth.

17 recordsLinked to original sources
PubMed2007

Osmium(II) and ruthenium(II) arene maltolato complexes: rapid hydrolysis and nucleobase binding.

Density functional calculations show that aquation of [Os(eta6-arene)(XY)Cl]n+ complexes is more facile for complexes in which XY=an anionic O,O-chelated ligand compared to a neutral N,N-chelated ligand, and the mechanism more dissociative in character. The O,O-chelated XY=maltolato (mal) [M(eta6-p-cym)(mal)Cl] complexes, in which p-cym=p-cymene, M=OsII (1) and RuII (2), were synthesised and the X-ray crystal structures of 1 and 22 H2O determined. Their hydrolysis rates were rapid (too fast to follow by NMR spectroscopy). The aqua adduct of the OsII complex 1 was 1.6 pKa units more acidic than that of the RuII complex 2. Dynamic NMR studies suggested that O,O-chelate ring opening occurs on a millisecond timescale in coordinating proton-donor solvents, and loss of chelated mal in aqueous solution led to the formation of the hydroxo-bridged dimers [(eta6-p-cym)M(mu-OH)3M(eta6-p-cym)]+. The proportion of this dimer in solutions of the OsII complex 1 increased with dilution and it predominated at micromolar concentrations, even in the presence of 0.1 M NaCl (conditions close to those used for cytotoxicity testing). Although 9-ethylguanine (9-EtG) binds rapidly to Os(II) in 1 and more strongly (log K=4.4) than to RuII in 2 (log K=3.9), the OsII adduct [Os(eta6-p-cym)(mal)(9EtG)]+ was unstable with respect to formation of the hydroxo-bridged dimer at micromolar concentrations. Such insights into the aqueous solution chemistry of metal-arene complexes under biologically relevant conditions will aid the rational design of organometallic anticancer agents.

Journal Article↗
PubMed2005

Controlling ligand substitution reactions of organometallic complexes: tuning cancer cell cytotoxicity.

Organometallic compounds offer broad scope for the design of therapeutic agents, but this avenue has yet to be widely explored. A key concept in the design of anticancer complexes is optimization of chemical reactivity to allow facile attack on the target site (e.g., DNA) yet avoid attack on other sites associated with unwanted side effects. Here, we consider how this result can be achieved for monofunctional "piano-stool" ruthenium(II) arene complexes of the type [(eta6-arene)Ru(ethylenediamine)(X)]n+. A potentially important activation mechanism for reactions with biomolecules is hydrolysis. Density functional calculations suggested that aquation (substitution of X by H2O) occurs by means of a concerted ligand interchange mechanism. We studied the kinetics and equilibria for hydrolysis of 21 complexes, containing, as X, halides and pseudohalides, pyridine (py) derivatives, and a thiolate, together with benzene (bz) or a substituted bz as arene, using UV-visible spectroscopy, HPLC, and electrospray MS. The x-ray structures of six complexes are reported. In general, complexes that hydrolyze either rapidly {e.g., X = halide [arene = hexamethylbenzene (hmb)]} or moderately slowly [e.g., X = azide, dichloropyridine (arene = hmb)] are active toward A2780 human ovarian cancer cells, whereas complexes that do not aquate (e.g., X = py) are inactive. An intriguing exception is the X = thiophenolate complex, which undergoes little hydrolysis and appears to be activated by a different mechanism. The ability to tune the chemical reactivity of this class of organometallic ruthenium arene compounds should be useful in optimizing their design as anticancer agents.

Antineoplastic Agents↗
PubMed2005

Molecular modelling of Jahn-Teller distortions in Cu(II)N6 complexes: elongations, compressions and the pathways in between.

Ligand Field Molecular Mechanics (LFMM) parameters have been optimised for six-coordinate Cu(II) complexes containing amine, pyridine, imidazole and pyrazine donors. As found in previous LFMM applications, the new parameters automatically generate distorted structures with the magnitudes of the Jahn-Teller elongations in good agreement with experiment. Here, we explore the rest of the potential energy surface. The introduction of axial strain drives the LFMM structures via rhombic geometries to the compressed structure, the latter corresponding to the saddle point between successive elongation axes. Calculated barrier heights between compressed and elongated geometries also agree well with available experimental data. In every case bar one, the LFMM predicts that the crystallographically observed elongation axis corresponds to the overall lowest energy well. The structural predictions are confirmed by independent density functional theory (DFT) optimisations. LFMM calculations on bis(2,5-pyrazolylpyridine)copper complexes display a smooth variation in structure as a function of pyrazolyl substituent from elongated for R = H through to fully compressed for R = (t)Bu. This behaviour is driven by the steric interactions with the ground state varying smoothly as a linear combination of {d(x2-y2)}1 and {d(z2)}1.

Journal Article↗
PubMed2005

Molecular modelling for coordination compounds: Cu(II)-amine complexes.

The Ligand Field Molecular Mechanics (LFMM) method has been applied to 85 Cu(II)-amine complexes, eighteen of which were selected to form a training set. A single set of parameters yields Cu-N bond lengths for four-, five- and six-coordinate systems generally within 0.04 A of their X-ray crystallographic values. Larger deviations are indicative of counterion effects and/or crystallographic artefacts arising from Jahn-Teller averaging. The LFMM treatment is flexible and unbiased and for simple ligands, automatically gives planar CuN(4) and tetragonally elongated CuN(6) complexes. In agreement with experiment, square-pyramidal coordination is marginally favoured over trigonal bipyramidal coordination for CuN(5) species. However, if the ligand requirements dictate, the LFMM accommodates trigonal bipyramidal coordination for CuN(5) species, tetrahedral distortions of CuN(4) species and cis-elongated CuN(6) species.

Journal Article↗
PubMed2005

Discovery of a new peptide natural product by Streptomyces coelicolor genome mining.

Analyses of microbial genome sequences reveal numerous examples of gene clusters encoding proteins typically involved in complex natural product biosynthesis but not associated with the production of known natural products. In Streptomyces coelicolor M145 there are several gene clusters encoding new nonribosomal peptide synthetase (NRPS) systems not associated with known metabolites. Application of structure-based models for substrate recognition by NRPS adenylation domains predicts the amino acids incorporated into the putative peptide products of these systems, but the accuracy of these predictions is untested. Here we report the isolation and structure determination of the new tris-hydroxamate tetrapeptide iron chelator coelichelin from S. coelicolor using a genome mining approach guided by substrate predictions for the trimodular NRPS CchH, and we show that this enzyme, which lacks a C-terminal thioesterase domain, together with a homolog of enterobactin esterase (CchJ), are required for coelichelin biosynthesis. These results demonstrate that accurate prediction of adenylation domain substrate selectivity is possible and raise intriguing mechanistic questions regarding the assembly of a tetrapeptide by a trimodular NRPS.

Computational Biology↗
PubMed2005

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 MOE's 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 [MCl)]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.

Journal Article↗
PubMed2004

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).

Journal Article↗
PubMed2004

Chiral metal architectures in aminopyridinato complexes of zirconium.

Optically pure 2-alkylaminopyridines (HL) are synthesised readily from bromopyridines and chiral amines [(S)-1,2,3,4-tetrahydro-1-naphthylamine and (S)-(-)-alpha-methylbenzylamine] using palladium-catalysed amination. Protonolysis reactions of these proligands with ZrX(4)(X = NMe(2), CH(2)Ph, CH(2)Bu(t)) yield zirconium aminopyridinates, usually of the type [ML(2)X(2)], some of which have been characterised by X-ray crystallography. Control of absolute configuration at the metal centre is pursued by investigation of the effects of chiral amine substituent, substitution at the pyridine rings and the identity of co-ligands. Surprisingly the conformationally flexible [small alpha]-methylbenzyl based aminopyridinato ligands promote much better control of chirality-at-zirconium than do the cyclic tetrahydronaphthyl analogues. One complex of the former class displays complete control of stereochemistry at 193 K; only one diastereomer out of eight possible structures is observed. It is found that there is an excellent correlation between observed selectivities and calculated diastereomer energy differences from DFT. All the complexes studied are in dynamic exchange between diastereomers. The rate of these processes (DeltaH ca. 40 kJ mol(-1)) as studied by Selective Polarisation Transfer-Selective Inversion Recovery experiments (SPT-SIR) and lineshape analyses are significantly faster than those for aminopyridines containing bulkier amido substituents (DeltaH ca. 70 kJ mol(-1)). This type of dependence on steric effects, and the impact of the trans effect, is consistent with an N-dissociative mechanism, i.e. conversion from six- to five-coordinate structure followed by rapid intramolecular scrambling.

Amines↗
PubMed2004

Electronic control of the regiochemistry in palladium-phosphine catalyzed intermolecular Heck reactions.

Density functional theory calculations of the transition-state structures and reaction barriers for the C-C coupling between monosubstituted eta(2)-olefins and eta(1)-vinyl for neutral [PdI(PH(3))(vinyl)(RCHCH(2))] and cationic [Pd(H(2)PCH(2)PH(2))(vinyl)(RCHCH(2))](+) (R = OMe, Me, and CN) depend mostly on the regiochemistry and not on the starting position of the olefin substituent. The regiochemistry is thus implicit in the electronic structure of the precursor complex. A selectivity index, Omega, based on electrostatic and frontier orbital interactions gives a good correlation with experiment for vinylations or arylations. The model correctly predicts that the regiochemistry for R = OMe, Me, and CN is the same for both neutral and cationic Pd complexes while for R = CH(2)OH the regiochemistry reverses. The latter is confirmed by explicit calculations of the transition-state energies. Selectivity indices are computed for 13 substituents: CO(2)Me, CN, CF(3), Ph, H, Me, CH(2)OH, CH(2)NMe(2), 2-pyrolidone, CH(2)SiMe(3), OAc, OMe, and F. Cationic conditions systematically give larger Omega values and thus tend to favor coupling at the alpha carbon on the olefin. The Omega values are approximately additive and can be used to predict the regiochemistry for disubstituted olefins.

Journal Article↗
PubMed2003

A density functional investigation of the extradiol cleavage mechanism in non-heme iron catechol dioxygenases.

The mechanism for extradiol cleavage in non-heme iron catechol dioxygenase was modelled theoretically via density functional theory. Based on the Fe(II)-His,His,Glu motif observed in enzymes, an active site model complex, [Fe(acetate)(imidazole)(2)(catecholate)(O(2))](-), was optimized for states with six, four and two unpaired electrons (U6, U4 and U2, respectively). The transfer of the terminal atom of the coordinated dioxygen leading to "ferryl" Fe=O intermediates spontaneously generates an extradiol epoxide. The computed barriers range from 19 kcal mol(-1) on the U6 surface to approximately 25 kcal mol(-1) on the U4 surface, with overall reaction energies of +11.6, 6.3 and 7.1 kcal mol(-1) for U6, U4 and U2, respectively. The calculations for a protonated process reveal the terminal oxygen of O(2) to be the thermodynamically favoured site but subsequent oxygen transfer to the catechol has a barrier of approximately 30-40 kcal mol(-1), depending on the spin state. Instead, protonating the acetate group gives a slightly higher energy species but a subsequent barrier on the U4 surface of only 7 kcal mol(-1) relative to the hydroperoxide complex. The overall exoergicity increases to 13 kcal mol(-1). The favoured proton-assisted pathway does not involve significant radical character and has features reminiscent of a Criegee rearrangement which involves the participation of the aromatic ring pi-orbitals in the formation of the new carbon-oxygen bond. The subsequent collapse of the epoxide, attack by the coordinated hydroxide and final product formation proceeds with an overall exoergicity of approximately 75 kcal mol(-1) on the U4 surface.

Catechols↗
PubMed2003

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.

Journal Article↗
PubMed2003

Ligand field and density functional descriptions of the d-states and bonding in transition metal complexes.

The d-orbital energy sequences for low symmetry transition metal complexes derived from Kohn-Sham density functional theory and ligand field theory are different due to each model's treatment of interelectron repulsion. The implications for providing a unified description of the underlying metal-ligand bonding are analysed and illustrated using conventional and time-dependent DFT. Previous detailed spectroscopic studies have established the d orbital sequence in planar coordination complexes containing pi-donor halide ligands as dx2-y2 >> dxy > dxz, dyz > dz2 while for a sigma-only system like [Pd(NH3)4]2+, ligand field approaches like the angular overlap model (AOM) or cellular ligand field (CLF) model predict dxz, dyz, and dxy, should be degenerate. However, the energies of the Kohn Sham (KS) 'd' orbitals of [PdCl4]2- and [Pd(NH3)4]2+ place dxy below the dxz/dyz pair. Direct use of the KS orbital eigenvalues in AOM or CLF analyses would imply both ligands are pi acceptors. This result is independent of the choice of functional or whether the calculation is carried out in vacuo or in a polarised continuum representing solvation by water. The origin of the difference between the KS and LFT d orbital sequences derives from their treatments of d-d interelectron repulsion. KS orbitals include interelectron repulsion contributions while LFT d orbitals do not. For a low-spin d8 complex, DFT gives less d-d interelectron repulsion in the xy plane leading to a lowering of dxy relative to dxy/dyz. This differential effect can be reversed qualitatively by progressively removing electron density from dz2 and placing it in dx2-y2. When about 0.6 electrons is rearranged, E(dxy) > E(dxz/dyz) for [PdCl4]2- and the dpi orbitals for [Pd(NH3)4]2+ are virtually degenerate. The wider ramifications of these interelectron repulsion effects are discussed for other symmetries. Excited d state energies for [PdCl4]2- are computed using both time dependent density functional theory (TDDFT) and determinant energies. The latter give the experimental sequence 1A2g < 1Eg < 1B1g while TDDFT gives 1Eg < 1A2g < 1B1g. Both give transition energies up to 30% lower than observed. A DFT analysis of the bonding energies in [PdCl4]2- indicates that the Pd-Cl pi bonding in the molecular plane is about 33% weaker than the out-of-plane pi interaction due to non-zero overlap between ligand orbitals. The normal LFT assumption of linear ligation may not always be valid.

Journal Article↗
PubMed2002

A density functional study of oxygen atom transfer reactions between biological oxygen atom donors and molybdenum(IV) bis(dithiolene) complexes.

Density functional calculations have been used to investigate oxygen atom transfer reactions from the biological oxygen atom donors trimethylamine N-oxide (Me(3)NO) and dimethyl sulfoxide (DMSO) to the molybdenum(IV) complexes [MoO(mnt)(2)](2-) and [Mo(OCH(3))(mnt)(2)](-) (mnt = maleonitrile-1,2-dithiolate), which may serve as models for mononuclear molybdenum enzymes of the DMSO reductase family. The reaction between [MoO(mnt)(2)](2-) and trimethylamine N-oxide was found to have an activation energy of 72 kJ/mol and proceed via a transition state (TS) with distorted octahedral geometry, where the Me(3)NO is bound through the oxygen to the molybdenum atom and the N-O bond is considerably weakened. The computational modeling of the reactions between dimethyl sulfoxide (DMSO) and [MoO(mnt)(2)](2-) or [Mo(OCH(3))(mnt)(2)](-) indicated that the former is energetically unfavorable while the latter was found to be favorable. The addition of a methyl group to [MoO(mnt)(2)](2-) to form the corresponding des-oxo complex not only lowers the relative energy of the products but also lowers the activation energy. In addition, the reaction with [Mo(OCH(3))(mnt)(2)](-) proceeds via a TS with trigonal prismatic geometry instead of the distorted octahedral TS geometry modeled for the reaction between [MoO(mnt)(2)](2-) and Me(3)NO.

Journal Article↗
PubMed2002

Six-coordinate Co(2+) with H(2)O and NH(3) ligands: which spin state is more stable?

Octahedral, six-coordinate Co(2+) can exist in two spin states. For biological ligands, H(2)O and NH(3), the most stable spin state is high spin (S = (3)/(2)). The difference in energy between high and low spin is dependent upon the ligand mix and coordination stereochemistry. High spin optimized geometries for these model compounds give structures close to octahedral symmetry. Low spin permits significant Jahn-Teller distortion. H(2)O ligands preferentially assume axial positions. Continuum solvent has a greater effect on low spin Co(2+), and it reduces the energy difference between the two spin states. For some ligand combinations optimized in the presence of solvent, there is no significant difference in energy between spin states.

Chemical Phenomena↗
PubMed2002

Efficient predetermination of chirality-at-zirconium.

Only one of eight possible diastereomers of the organometallic chiral-at-metal complex [ZrL2(CH2Ph)2] (L = a bidentate, chiral non-racemic pyrdine alcoholate) is observed by NMR spectroscopy in the slow exchange regime.

Journal Article↗
PubMed2002

An unexpected [1,5]-h shift in the synthesis of nitroanilines.

Addition of methyl acetoacetate to 2-nitrovinamidinium hexafluorophosphate salts leads to the formation of anilines or phenols in good to excellent yields depending on the alkylamine substituents. Small substituents, e.g., pyrrolidine, lead to the formation of anilines while large substituents, e.g., N,N-diisopropyl, exclusively give phenols. Labeling studies implicate a [1,5]-H shift proceeding with excellent isotopic fidelity.

Journal Article↗