Antimalarial drugs based on artemisinin: DFT calculations on the principal reactions

Theoretical calculations have been carried out on the interactions of several endoperoxides which are potential antimalarials, including the clinically useful artemisinin, with two possible sources of iron in the parasite, namely the hexa-aquo ferrous ion [Fe(H2O)(6)](2+) and haeme. DFT calculations show that the reactions of all endoperoxides considered, with both sources of iron, initially generate a Fe-O bond followed by cleavage of the O-O bond to oxygen radical species. Subsequently, they can be transformed into carbon-centred radicals of greater stability. However, with [Fe(H2O)(6)](2+) as the iron source, the oxygen-centred radical species are more likely to react further akin to Fenton's reagent, whereby iron salts encourage hydrogen peroxide to act as an oxidizing agent, and that solvent plays a major role. In contrast, when reacting with haeme, the oxygen-centred radicals interconvert to more stable carbon-centred radicals, which can then alkylate haeme. Subsequent cleavage of the Fe-O bond leads to stable and inactive antimalarial products. These results indicate that the reactivity of the endoperoxides as antimalarials is greater with iron hexahydrates for radical-mediated damage as opposed to haeme, which leads to unreactive species. Since only nanomolar quantities of hydrated metal ions could catalyse the reactions leading to damage to the parasites, this could be an alternative or competitive reaction responsible for the antimalarial activity. (c) 2005 Elsevier B.V. All rights reserved.

Tuning of redox potential and visible absorption band of ruthenium(II) complexes of (benzimidazolyl) derivatives: synthesis, characterization, spectroscopic and redox properties, X-ray structures and DFT calculations

Six ruthenium(II) complexes have been prepared using the tridentate ligands 2,6-bis(benzimidazolyl) pyridine and bis(2-benzimidazolyl methyl) amine and having 2,2'-bipyridine, 2,2':6',2 ''-terpyridine, PPh3, MeCN and chloride as coligands. The crystal structures of three of the complexes trans-[Ru(bbpH(2))(PPh3)(2)(CH3CN)I(ClO4)(2) center dot 2H(2)O (2), [Ru(bbpH(2))(bpy)Cl]ClO4 (3) and [Ru(bbpH(2))(terpy)](ClO4)(2) (4) are also reported. The complexes show visible region absorption at 402-517 nm, indicating that it is possible to tune the visible region absorption by varying the ancillary ligand. Luminescence behavior of the complexes has been studied both at RT and at liquid nitrogen temperature (LNT). Luminescence of the complexes is found to be insensitive to the presence of dioxygen. Two of the complexes [Ru(bbpH(2))(bpy)Cl]ClO4 (3) and [Ru(bbpH(2))(terpy]ClO4)(2) (4) show RT emission in the NIR region, having lifetime, quantum yield and radiative constant values suitable for their application as NIR emitter in the solid state devices. The DFT calculations on these two complexes indicate that the metal t(2g) electrons are appreciably delocalized over the ligand backbone. (C) 2006 Elsevier B.V. All rights reserved.

Syntheses, x-ray structures, photochemistry, redox properties, and DFT calculations of interconvertible fac- and mer-[Mn(SPS)(CO)3] isomers containing a flexible SPS-based pincer ligand

The lithium salt of the anionic SPS pincer ligand composed of a central hypervalent lambda(4)-phosphinine ring bearing two ortho-positioned diphenylphosphine sulfide side arms reacts with [Mn(CO)(5)Br] to give fac-[Mn(SPS)(CO)(3)], This isomer can be converted photochemicaily to mer-[Mn(SPS)(CO)(3)], with a very high quantum yield (0.80 +/- 0.05). The thermal backreaction is slow (taking ca. 8 h at room temperature), in contrast to rapid electrodecatalyzed mer-to-fac isomerization triggered by electrochemical reduction of mer-[Mn(SPS)(CO)(3)]. Both geometric isomers of [Mn(SPS)(CO)(3)] have been characterized by X-ray crystallography. Both isomers show luminescence from a low-lying (IL)-I-3 (SPS-based) excited state. The light emission of fac-[Mn(SPS)(CO)(3)] is largely quenched by the efficient photoisomerization occurring probably from a low-lying Mn-CO dissociative excited state. Density functional theory (DFT) and time-dependent DFT calculations describe the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) of fac- and mer-[Mn(CO)(3)(SPS)] as ligand-centered orbitals, largely localized on the phosphinine ring of the SPS pincer ligand. In line with the ligand nature of its frontier orbitals, fac-[Mn(SPS)(CO)(3)] is electrochemically reversibly oxidized and reduced to the corresponding radical cation and anion, respectively. The spectroscopic (electron paramagnetic resonance, IR, and UV-vis) characterization of the radical species provides other evidence for the localization of the redox steps on the SIPS ligand. The smaller HOMO-LUMO energy difference in the case of mer-[Mn(CO)(3)(SPS)], reflected in the electronic absorption and emission spectra, corresponds with its lower oxidation potential compared to that of the fac isomer. The thermodynamic instability of mer-[Mn(CO)(3)(SPS)], confirmed by the DFT calculations, increases upon one-electron reduction and oxidation of the complex.

Excited states of nitro-polypyridine metal complexes and their ultrafast decay. Time-resolved IR absorption, spectroelectrochemistry, and TD-DFT calculations of fac-[Re(Cl)(CO)3(5-Nitro-1,10-phenanthroline)]

The lowest absorption band of fac-[Re(Cl)(CO)(3)(5-NO2-phen)] encompasses two close-lying MLCT transitions. The lower one is directed to LUMO, which is heavily localized on the NO2 group. The UV-vis absorption spectrum is well accounted for by TD-DFT (G03/PBEPBE1/CPCM), provided that the solvent, MeCN, is included in the calculations. Near-UV excitation of fac-[Re(Cl)(CO)(3)(5-NO2-phen)] populates a triplet metal to ligand charge-transfer excited state, (MLCT)-M-3, that was characterized by picosecond time-resolved IR spectroscopy. Large positive shifts of the v(CO) bands upon excitation (+70 cm(-1) for the A'(1) band) signify a very large charge separation between the Re(Cl)(CO)3 unit and the 5-NO2-phen ligand. Details of the excited-state character are revealed by TD-DFT calculated changes of electron density distribution. Experimental excited-state v(CO) wavenumbers agree well with those calculated by DFT. The (MLCT)-M-3 state decays with a ca. 10 ps lifetime (in MeCN) into another transient species, that was identified by TRIR and TD-DFT calculations as an intraligand (3)n pi* excited state, whereby the electron density is excited from the NO2 oxygen lone pairs to the pi* system of 5-NO2-phen. This state is short-lived, decaying to the ground state with a similar to 30 ps lifetime. The presence of an n pi* state seems to be the main factor responsible for the lack of emission and the very short lifetimes of 3 MLCT states seen in all d(6)-metal complexes of nitro-polypyridyl ligands. Localization of the excited electron density in the lowest (MLCT)-M-3 states parallels localization of the extra electron in the reduced state that is characterized by a very small negative shift of the v(CO) IR bands (-6 cm(-1) for A'(1)) but a large downward shift of the v(s)(NO2) IR band. The Re-Cl bond is unusually stable toward reduction, whereas the Cl ligand is readily substituted upon oxidation.

Modeling the tetraphenylalanine-PEG hybrid amphiphile: from DFT calculations on the peptide to molecular dynamics simulations on the conjugate

The conformational properties of the hybrid amphiphile formed by the conjugation of a hydrophobic peptide with four phenylalanine (Phe) residues and hydrophilic poly(ethylene glycol), have been investigated using quantum mechanical calculations and atomistic molecular dynamics simulations. The intrinsic conformational preferences of the peptide were examined using the building-up search procedure combined with B3LYP/ 6-31G(d) geometry optimizations, which led to the identification of 78, 78, and 92 minimum energy structures for the peptides containing one, two, and four Phe residues. These peptides tend to adopt regular organizations involving turn-like motifs that define ribbon or helicallike arrangements. Furthermore, calculations indicate that backbone ... side chain interactions involving the N-H of the amide groups and the pi clouds of the aromatic rings play a crucial role in Phe-containing peptides. On the other hand,MD simulations on the complete amphiphile in aqueous solution showed that the polymer fragment rapidly unfolds maximizing the contacts with the polar solvent, even though the hydrophobic peptide reduce the number of waters of hydration with respect to an individual polymer chain of equivalent molecular weight. In spite of the small effect of the peptide in the hydrodynamic properties of the polymer, we conclude that the two counterparts of the amphiphile tend to organize as independent modules.

Diorganoruthenium complexes incorporating noninnocent [C6H2(CH2ER2)2-3,5]22-(E = N, P) Bis-Pincer bridging ligands: synthesis, spectroelectrochemistry, and DFT studies

The dinuclear complex [(tpy)Ru-II(PCP-PCP)Ru-II(tPY)]Cl-2 (bridging PCP-PCP = 3,3',5,5'-tetrakis(diphenylphosphinomethyl)biphenyl, [C6H2(CH2PPh2)(2)-3,5](2)(2-)) was prepared via a transcyclometalation reaction of the bis-pincer ligand [PC(H)P-PC(H)P] and the Ru(II) precursor [Ru(NCN)(tpy)]Cl (NCN = [C6H3(CH2NMe2)(2)-2,6](-)) followed by a reaction with 2,2':6',2 ''-terpyridine (tpy). Electrochemical and spectroscopic properties of [(tpy)Ru-II(PCP-PCP)Ru-II(tPY)]Cl-2 are compared with those of the closely related [(tpy)Ru-II(NCN-NCN)Ru-II(tpy)](PF6)(2) (NCN-NCN = [C6H2(CH2- NMe2)(2)-3,5](2)(2-)) obtained by two-electron reduction of [(tpy)Ru-III(NCN-NCN)Ru-III(tpy)](PF6)(4). The molecular structure of the latter complex has been determined by single-crystal X-ray structure determination. One-electron reduction of [(tpy)Ru-III(NCN-NCN)Ru-III(tpy)](PF6)(4) and one-electron oxidation of [(tpy)Ru-II(PCP-PCP)RUII(tpy)]Cl-2 yielded the mixed-valence species [(tpy)Ru-III(NCN-NCN)RUII(tpy)](3+) and [(tpy)Ru-III(PCP-PCP)RUII(tpy)](3+), respectively. The comproportionation equilibrium constants K-c (900 and 748 for [(tpy)Ru-III(NCN-NCN)Ru-III(tpy)](4+) and [(tpy)Ru-II(PCP-PCP)RUII(tpy)](2+), respectively) determined from cyclic voltammetric data reveal comparable stability of the [Ru-III-Ru-II] state of both complexes. Spectroelectrochemical measurements and near-infrared (NIR) spectroscopy were employed to further characterize the different redox states with special focus on the mixed-valence species and their NIR bands. Analysis of these bands in the framework of Hush theory indicates that the mixed-valence complexes [(tpy)Ru-III(PCP-PCP)RUII(tpy)](3+) and [(tpy)Ru-III(NCN-NCN)RUII(tpy)](3+) belong to strongly coupled borderline Class II/Class III and intrinsically coupled Class III systems, respectively. Preliminary DFT calculations suggest that extensive delocalization of the spin density over the metal centers and the bridging ligand exists. TD-DFT calculations then suggested a substantial MLCT character of the NIR electronic transitions. The results obtained in this study point to a decreased metal-metal electronic interaction accommodated by the double-cyclometalated bis-pincer bridge when strong sigma-donor NMe2 groups are replaced by weak sigma-donor, pi-acceptor PPh2 groups

Molecular structures and electronic transitions of 3,6-Diphenyl-1,2-dithiin and its radical cation: a spectroelectrochemical and DFT study

One-electron oxidation of 3,6-diphenyl-1,2-dithiin yields the corresponding radical cation. The product is stable at low temperatures and can be distinguished by a triplet EPR signal. Cyclic voltammetric, UV-vis spectroelectrochemical, and DFT studies were performed to elucidate its molecular structure and electronic properties. Time-dependent DFT calculations reproduce appreciably well the UV-vis spectral changes observed during the oxidation. The results reveal a moderately twisted structure of the 1,2-dithiin heterocycle in the radical cation.

A new interpretation of the bonding properties and UV–vis spectra of [M3(CO)12] clusters (M = Ru, Os): a TD-DFT study

DFT and TD-DFT calculations (ADF program) were performed in order to analyze the electronic structure of the [M-3(CO)(12)] clusters (M = Ru, Os) and interpret their electronic spectra. The highest occupied molecular orbitals are M-M bonding (sigma) involving different M-M bonds, both for Ru and Os. They participate in low-energy excitation processes and their depopulation should weaken M-M bonds in general. While the LUMO is M-NI and M-CO anti-bonding (sigma*), the next, higher-lying empty orbitals have a main contribution from CO (pi*) and either a small (Ru) or an almost negligible one (Os) from the metal atoms. The main difference between the two clusters comes from the different nature of these low-energy unoccupied orbitals that have a larger metal contribution in the case of ruthenium. The photochemical reactivity of the two clusters is reexamined and compared to earlier interpretations.

Nickel(II) and copper(II) complexes of Schiff base ligands containing N4O2 and N4S2 donors with pyrrole terminal binding groups: synthesis, characterization, X-ray structures, DFT and electrochemical studies

A series of hexadentate ligands, H2Lm (m = 1−4), [1H-pyrrol-2-ylmethylene]{2-[2-(2-{[1H-pyrrol-2-ylmethylene]amino}phenoxy)ethoxy]phenyl}amine (H2L1), [1H-pyrrol-2-ylmethylene]{2-[4-(2-{[1H-pyrrol-2-ylmethylene]amino}phenoxy)butoxy]phenyl}amine (H2L2), [1H-pyrrol-2-ylmethylene][2-({2-[(2-{[1H-pyrrol-2-ylmethylene]amino}phenyl)thio]ethyl}thio)phenyl]amine (H2L3) and [1H-pyrrol-2-ylmethylene][2-({4-[(2-{[1H-pyrrol-2-lmethylene]amino}phenyl)thio]butyl}thio) phenyl]amine (H2L4) were prepared by condensation reaction of pyrrol-2-carboxaldehyde with {2-[2-(2-aminophenoxy)ethoxy]phenyl}amine, {2-[4-(2-aminophenoxy)butoxy]phenyl}amine, [2-({2-[(2-aminophenyl)thio]ethyl}thio)phenyl]amine and [2-({4-[(2-aminophenyl)thio]butyl}thio)phenyl]amine respectively. Reaction of these ligands with nickel(II) and copper(II) acetate gave complexes of the form MLm (m = 1−4), and the synthesized ligands and their complexes have been characterized by a variety of physico-chemical techniques. The solid and solution states investigations show that the complexes are neutral. The molecular structures of NiL3 and CuL2, which have been determined by single crystal X-ray diffraction, indicate that the NiL3 complex has a distorted octahedral coordination environment around the metal while the CuL2 complex has a seesaw coordination geometry. DFT calculations were used to analyse the electronic structure and simulation of the electronic absorption spectrum of the CuL2 complex using TDDFT gives results that are consistent with the measured spectroscopic behavior of the complex. Cyclic voltammetry indicates that all copper complexes are electrochemically inactive but the nickel complexes with softer thioethers are more easily oxidized than their oxygen analogs.

Coverage-dependent molecular tilt of carbon monoxide chemisorbed on Pt{110}: A combined LEED and DFT structural analysis

The adsorption of carbon monoxide on the Pt{110} surface at coverages of 0.5 ML and 1.0 ML was investigated using quantitative low-energy electron diffraction (LEED IV) and density-functional theory (DFT). At 0.5 ML CO lifts the reconstruction of the clean surface but does not form an ordered overlayer. At the saturation coverage, 1.0 ML, a well-ordered p(2×1) superstructure with glide line symmetry is formed. It was confirmed that the CO molecules adsorb on top of the Pt atoms in the top-most substrate layer with the molecular axes tilted by ±22° with respect to the surface normal in alternating directions away from the close packed rows of Pt atoms. This is accompanied by significant lateral shifts of 0.55 Å away from the atop sites in the same direction as the tilt. The top-most substrate layer relaxes inwards by −4% with respect to the bulk-terminated atom positions, while the consecutive layers only show minor relaxations. Despite the lack of long-range order in the 0.5 ML CO layer it was possible to determine key structural parameters by LEED IV using only the intensities of the integer-order spots. At this coverage CO also adsorbs on atop sites with the molecular axis closer to the surface normal (b10°). The average substrate relaxations in each layer are similar for both coverages and consistent with DFT calculations performed for a variety of ordered structures with coverages of 1.0 ML and 0.5 ML.

1,1′-Bis(diphenylphosphino)ferrocene bridging two mono(cyclopentadienyl) cobalt moieties: synthesis, structure, electrochemistry and DFT studies

Reaction of [Co(eta(5)-C5H5)(CO)(2)], 1, with 1,1'-bis(diphenylphosphino)ferrocene (dppf) yields the new trinuclear complex [Co(eta(5)-C5H5)(CO)](2)(mu-dppf), 2, which was structurally characterised by single crystal X-ray diffraction and showed two Co(eta(5)-C5H5)(CO) moieties covalently linked by a dppf bridge. Electrochemical studies in dichloromethane revealed that both Co(I) and Fe(II) in the precursors were oxidized to Co(II)/Co(III) and Fe(III), respectively. On the other hand, in 2 the two first oxidation waves were assigned to Co, the Fe(II) centre requiring a higher potential than in free dppf. DFT calculations showed that the HOMOs of 2 were localised in the Co fragments, owing to the destabilisation of the Co(eta(5)-C5H5)(CO) orbitals after binding dppf.

Synthesis, chemical, electrochemical characterization of oxomolybdenum(V) complexes of 2-(3,5-dimethyl pyrazol-1-yl) benzothiazole ligand: crystal structure of ligand and oxomolybdenum(VI) complex and density functional theory (DFT) calculation

This work reports the ligational behavior of the neutral bidentate chelating molecule 2-(3,5-dimethyl pyrazol-1-yl) benzothiazole towards the oxomolybdenum(V) center. Both mononuclear complexes of the type (MoOX3L)-O-V and binuclear complexes of the formula (Mo2O4X2L2)-O-V (where X = Cl, Br) are isolated in the solid state. The complexes are characterized by elemental analyses, various spectroscopic techniques (UV-Vis IR), magnetic susceptibility measurement at room temperature, and cyclic voltammetry for their redox behavior at a platinum electrode in CH3CN. The mononuclear complexes (MoOX3L)-O-V are found to be paramagnetic while the binuclear complexes Mo2O4X2L2 are diamagnetic. Crystal and molecular structure of the ligand and the dioxomolybdenum complex (MoO2Br2L)-O-VI (obtained from the complex MoOBr3L during crystallization) have been solved by single crystal X-ray diffraction technique. Relevant DFT calculations of the ligand and the complex (MoO2Br2L)-O-VI are also carried out.

Diruthenium complexes with bridging diethynyl polyaromatic ligands: synthesis, spectroelectrochemistry, and theoretical calculations

This work describes syntheses and electrochemical, spectroscopic, and bonding properties in a new series of dinuclear ruthenium(II) complexes bridged by polyaromatic (biphenyl, fluorene, phenanthrene, and pyrene) alkynyl ligands. Longitudinal expansion of the π-conjugated polyaromatic core of the bridging ligands caused a reduced potential difference between the anodic steps and reinforced their bridge-localized nature, as evidenced by UV/vis/near-IR and IR spectroelectrochemical data combined with DFT and TDDFT calculations. Importantly, the intricate multiple IR ν(CC) absorption bands for the singly oxidized states imply a thermal population of a range of conformers (rotamers) with distinct electronic character. This behavior was demonstrated with more accurate DFT calculations of selected nontruncated 1e− oxidized complexes in three different conformations. The combined experimental and theoretical data reveal that thermally populated rotamers featuring various mutual orientations of the ligated metal termini and the bridging diethynyl polyaromatic moieties have a significant impact on the electronic absorption and ν(CC) wavenumbers of the singly oxidized systems.

Direct detection of dimethylstannylene and tetramethyldistannene in solution and the gas phase by laser flash photolysis of 1,1-dimethylstannacyclopent-3-enes

The photochemistry of 1,1-dimethyl- and 1,1,3,4-tetramethylstannacyclopent-3-ene (4a and 4b,respectively) has been studied in the gas phase and in hexane solution by steady-state and 193-nm laser flash photolysis methods. Photolysis of the two compounds results in the formation of 1,3-butadiene (from 4a) and 2,3-dimethyl-1,3-butadiene (from 4b) as the major products, suggesting that cycloreversion to yield dimethylstannylene (SnMe2) is the main photodecomposition pathway of these molecules. Indeed, the stannylene has been trapped as the Sn-H insertion product upon photolysis of 4a in hexane containing trimethylstannane. Flash photolysis of 4a in the gas phase affords a transient absorbing in the 450-520nm range that is assigned to SnMe2 by comparison of its spectrum and reactivity to those previously reported from other precursors. Flash photolysis of 4b in hexane solution affords results consistent with the initial formation of SnMe2 (lambda(max) approximate to 500 nm), which decays over similar to 10 mu s to form tetramethyldistannene (5b; lambda(max) approximate to 470 nm). The distannene decays over the next ca. 50 mu s to form at least two other longer-lived species, which are assigned to higher SnMe2 oligomers. Time-dependent DFT calculations support the spectral assignments for SnMe2 and Sn2Me4, and calculations examining the variation in bond dissociation energy with substituent (H, Me, and Ph) in disilenes, digermenes, and distannenes rule out the possibility that dimerization of SnMe2 proceeds reversibly. Addition of methanol leads to reversible reaction with SnMe2 to form a transient absorbing at lambda(max) approximate to 360 nm, which is assigned to the Lewis acid-base complex between SnMe2 and the alcohol.

Effect of H-bonding on the ambivalence of SCN- towards copper(II)

Condensations of 2-(2-aminoethyl)pyridine with 4-methylimidazole-5-carboxaldehyde and 1-methyl-2-imidazolecarboxaldehyde generate the tridentate N donor ligands L and L' respectively. Reactions of Cu(NCS)(2) with L and L' yield respectively CuL(SCN)(NCS) (1) containing a CuN4S core and CuL'(NCS)(2) (2) having a CuN5 core. Both the cores are square pyramidal with SCN bound in 1 at the axial position through the S end. This differential behaviour of SCN in the two complexes despite the ligands being very similar, is investigated by DFT calculations at the B3LYP/TZV level. It is found that DFT calculations predict isolation of the Cu(ligand)(NCS)(2) species for both the ligands L and L'. Presence of an offsetting intermolecular H-bonding between the N atom of the thiocyanate and the N-H proton of the ligand L of an adjacent molecule makes the binding of SCN via the S end feasible in 1 resulting in the H-bonded-dimer Cu2L2(SCN)(2)(NCS)(2). The strength of the H-bond is estimated as 27.1 kJ mol (1) from the DFT calculations. The question of such H-bonding does not arise with L' as it lacks in a similar H atom. Dimeric 1 represents a case of two non-interacting spins. (C) 2008 Elsevier B. V. All rights reserved.