Unprecedented Mo3S4 cluster-catalyzed radical C-C cross-coupling reactions of aryl alkynes and acrylates.

A new method for the generation of benzyl radicals from terminal aromatic alkynes has been developed, which allows the direct cross coupling with acrylate derivatives. Our additive-free protocol employs air-stable diamino Mo3S4 cubane-type cluster catalysts in the presence of hydrogen. A sulfur-centered cluster catalysis mechanism for benzyl radical formation is proposed based on catalytic and stoichiometric experiments. The process starts with the cluster hydrogen activation to form a bis(hydrosulfido) [Mo3(µ3-S)(µ-S)(µ-SH)2Cl3(dmen)3]+ intermediate. The reaction of various aromatic terminal alkynes containing different functionalities with a series of acrylates affords the corresponding Giese-type radical addition products.

Spin-Crossing in the (Z)-Selective Alkyne Semihydrogenation Mechanism Catalyzed by Mo3S4 Clusters: A Density Functional Theory Exploration.

Semihydrogenation of internal alkynes catalyzed by the air-stable imidazolyl amino [Mo3S4Cl3(ImNH2)3]+ cluster selectively affords the (Z)-alkene under soft conditions in excellent yields. Experimental results suggest a sulfur-based mechanism with the formation of a dithiolene adduct through interaction of the alkyne with the bridging sulfur atoms. However, computational studies indicate that this mechanism is unable to explain the experimental outcome: mild reaction conditions, excellent selectivity toward the (Z)-isomer, and complete deuteration of the vinylic positions in the presence of CD3OD and CH3OD. An alternative mechanism that explains the experimental results is proposed. The reaction begins with the hydrogenation of two of the Mo3(µ3-S)(µ-S)3 bridging sulfurs to yield a bis(hydrosulfide) intermediate that performs two sequential hydrogen atom transfers (HAT) from the S-H groups to the alkyne. The first HAT occurs with a spin change from singlet to triplet. After the second HAT, the singlet state is recovered. Although the dithiolene adduct is more stable than the hydrosulfide species, the large energy required for the subsequent H2 addition makes the system evolve via the second alternative pathway to selectively render the (Z)-alkene with a lower overall activation barrier.

Base-Free Catalytic Hydrogen Production from Formic Acid Mediated by a Cubane-Type Mo3S4 Cluster Hydride.

Formic acid (FA) dehydrogenation is an attractive process in the implementation of a hydrogen economy. To make this process greener and less costly, the interest nowadays is moving toward non-noble metal catalysts and additive-free protocols. Efficient protocols using earth abundant first row transition metals, mostly iron, have been developed, but other metals, such as molybdenum, remain practically unexplored. Herein, we present the transformation of FA to form H2 and CO2 through a cluster catalysis mechanism mediated by a cuboidal [Mo3S4H3(dmpe)3]+ hydride cluster in the absence of base or any other additive. Our catalyst has proved to be more active and selective than the other molybdenum compounds reported to date for this purpose. Kinetic studies, reaction monitoring, and isolation of the [Mo3S4(OCHO)3(dmpe)3]+ formate reaction intermediate, in combination with DFT calculations, have allowed us to formulate an unambiguous mechanism of FA dehydrogenation. Kinetic studies indicate that the reaction at temperatures up to 60 °C ends at the triformate complex and occurs in a single kinetic step, which can be interpreted in terms of statistical kinetics at the three metal centers. The process starts with the formation of a dihydrogen-bonded species with Mo-H···HOOCH bonds, detected by NMR techniques, followed by hydrogen release and formate coordination. Whereas this process is favored at temperatures up to 60 °C, the subsequent ß-hydride elimination that allows for the CO2 release and closes the catalytic cycle is only completed at higher temperatures. The cycle also operates starting from the [Mo3S4(OCHO)3(dmpe)3]+ formate intermediate, again with preservation of the cluster integrity, which adds our proposal to the list of the infrequent cluster catalysis reaction mechanisms.

On the catalytic transfer hydrogenation of nitroarenes by a cubane-type Mo3S4 cluster hydride: disentangling the nature of the reaction mechanism.

Cubane-type Mo3S4 cluster hydrides decorated with phosphine ligands are active catalysts for the transfer hydrogenation of nitroarenes to aniline derivatives in the presence of formic acid (HCOOH) and triethylamine (Et3N). The process is highly selective and most of the cluster species involved in the catalytic cycle have been identified through reaction monitoring. Formation of a dihydrogen cluster intermediate has also been postulated based on previous kinetic and theoretical studies. However, the different steps involved in the transfer hydrogenation from the cluster to the nitroarene to finally produce aniline remain unclear. Herein, we report an in-depth computational investigation into this mechanism. Et3N reduces the activation barrier associated with the formation of Mo-HHOOCH dihydrogen species. The global catalytic process is highly exergonic and occurs in three consecutive steps with nitrosobenzene and N-phenylhydroxylamine as reaction intermediates. Our computational findings explain how hydrogen is transferred from these Mo-HHOOCH dihydrogen adducts to nitrobenzene with the concomitant formation of nitrosobenzene and the formate substituted cluster. Then, a ß-hydride elimination reaction accompanied by CO2 release regenerates the cluster hydride. Two additional steps are needed for hydrogen transfer from the dihydrogen cluster to nitrosobenzene and N-phenylhydroxylamine to finally produce aniline. Our results show that the three metal centres in the Mo3S4 unit act independently, so the cluster can exist in up to ten different forms that are capable of opening a wide range of reaction paths. This behaviour reveals the outstanding catalytic possibilities of this kind of cluster complexes, which work as highly efficient catalytic machines.

C3-symmetry Mo3S4 aminophosphino clusters combining three sources of stereogenicity: stereocontrol directed by hydrogen bond interactions and ligand configuration.

A diastereoselective synthesis of proline containing aminophosphino cubane-type Mo3S4 clusters, (P)-[Mo3S4Cl3((1S,2R)-PPro)3]Cl (Cl) and (P)-[Mo3S4Cl3((1S,2S)-PPro)3]Cl (Cl), has been achieved in high yields by reacting the corresponding enantiomerically pure PPro ((R)- and (S)-2-[(diphenylphosphino)methyl]pyrrolidine) ligands with the Mo3S4Cl4(PPh3)3(H2O)2 complex. Circular dichroism, nuclear magnetic resonance and X-ray techniques confirm that the Cl and Cl cluster cations are diastereoisomers which combine three sources of stereogenicity provided by the cluster framework, one carbon atom of the aminophosphine ligand and the nitrogen stereogenic center. The higher stability of the (+) cation is due to stabilizing vicinal ClHN interactions as well as due to the cis-fused conformation of the bicyclic system formed upon coordination of the aminophosphine ligand.

Splicing regulator SLU7 preserves survival of hepatocellular carcinoma cells and other solid tumors via oncogenic miR-17-92 cluster expression.

Resisting death is a central hallmark of cancer cells. Tumors rely on a number of genetic mechanisms to avoid apoptosis, and alterations in mRNA alternative splicing are increasingly recognized to have a role in tumorigenesis. In this study, we identify the splicing regulator SLU7 as an essential factor for the preservation of hepatocellular carcinoma (HCC) cells viability. Compared with hepatocytes, SLU7 expression is reduced in HCC cells; however, further SLU7 depletion triggered autophagy-related cellular apoptosis in association with the overproduction of reactive oxygen species. Remarkably, these responses were not observed in primary human hepatocytes or in the well-differentiated HepaRG cell line. Mechanistically, we demonstrate that SLU7 binds the C13orf25 primary transcript in which the polycistronic oncomir miR-17-92 cluster is encompassed, and is necessary for its processing and expression. SLU7 knockdown altered the splicing of the C13orf25 primary transcript, and markedly reduced the expression of its miR-17, miR-20 and miR-92a constituents. This led to the upregulation of CDKN1A (P21) and BCL2L11 (BIM) expression, two bona fide targets of the miR-17-92 cluster and recognized mediators of its pro-survival and tumorigenic activity. Interestingly, altered splicing of miR-17-92 and downregulation of miR-17 and miR-20 were not observed upon SLU7 knockdown in non-transformed hepatocytes, but was found in other (HeLa, H358) but not in all (Caco2) non-hepatic tumor cells. The functional relevance of miR-17-92 dysregulation upon SLU7 knockdown was established when oxidative stress, autophagy and apoptosis were reversed by co-transfection of HCC cells with a miR-17 mimic. Together, these findings indicate that SLU7 is co-opted by HCC cells and other tumor cell types to maintain survival, and identify this splicing regulator as a new determinant for the expression of the oncogenic miR-17-92 cluster. This novel mechanism may be exploited for the development of antitumoral strategies in cancers displaying such SLU7-miR-17-92 crosstalk.

Inquiry of the electron density transfers in chemical reactions: a complete reaction path for the denitrogenation process of 2,3-diazabicyclo[2.2.1]hept-2-ene derivatives.

A detailed study on all stages associated with the reaction mechanisms for the denitrogenation of 2,3-diazabicyclo[2.2.1]hept-2-ene derivatives (DBX, with X substituents at the methano-bridge carbon atom, X = H and OH) is presented. In particular, we have characterized the processes leading to cycloalkene derivatives through migration-type mechanisms as well as the processes leading to cyclopentil-1,3-diradical species along concerted or stepwise pathways. The reaction mechanisms have been further analysed within the bonding evolution theory framework at B3LYP and M05-2X/6-311+G(2d,p) levels of theory. Analysis of the results allows us to obtain the intimate electronic mechanism for the studied processes, providing a new topological picture of processes underlying the correlation between the experimental measurements obtained by few-optical-cycle visible pulse radiation and the quantum topological analysis of the electron localization function (ELF) in terms of breaking/forming processes along this chemical rearrangement. The evolution of the population of the disynaptic basin V(N1,N2) can be related to the experimental observation associated with the N=N stretching mode evolution, relative to the N2 release, along the reaction process. This result allows us to determine why the N2 release is easier for the DBH case via a concerted mechanism compared to the stepwise mechanism found in the DBOH system. This holds the key to unprecedented insight into the mapping of the electrons making/breaking the bonds while the bonds change.

Synthesis and structure of trinuclear W3S4 clusters bearing aminophosphine ligands and their reactivity toward halides and pseudohalides.

The aminophosphine ligand (2-aminoethyl)diphenylphosphine (edpp) has been coordinated to the W3(µ-S)(µ-S)3 cluster unit to afford trimetallic complex [W3S4Br3(edpp)3](+) (1(+)) in a one-step synthesis process with high yields. Related [W3S4X3(edpp)3](+) clusters (X = F(-), Cl(-), NCS(-); 2(+)-4(+)) have been isolated by treating 1(+) with the corresponding halide or pseudohalide salt. The structure of complexes 1(+) to 4(+) contains an incomplete W3S4 cubane-type cluster unit, and only one of the possible isomers is formed: the one with the phosphorus atoms trans to the capping sulfur and the amino groups trans to the bridging sulphurs. The remaining coordination position on each metal is occupied by X. Detailed studies using stopped-flow, (31)P{(1)H} NMR, and ESI-MS have been carried out in order to understand the solution behavior and the kinetics of interconversion among species 1(+), 2(+), 3(+), and 4(+) in solution. Density functional theory (DFT) calculations have been also carried out on the reactions of cluster 1(+) with the different anions. The whole set of experimental and theoretical data indicate that the actual mechanism of substitutions in these clusters is strongly dependent on the nature of the leaving and entering anions. The interaction between an entering F(-) and the amino group coordinated to the adjacent metal have also been found to be especially relevant to the kinetics of these reactions.

A gene signature of bone metastatic colonization sensitizes for tumor-induced osteolysis and predicts survival in lung cancer.

Bone metastasis of lung adenocarcinoma (AC) is a frequent complication of advanced disease. The purpose of this study was to identify key mediators conferring robust prometastatic activity with clinical significance. We isolated highly metastatic subpopulations (HMS) using a previously described in vivo model of lung AC bone metastasis. We performed transcriptomic profiling of HMS and stringent bioinformatics filtering. Functional validation was assessed by overexpression and lentiviral silencing of single, double and triple combination in vivo and in vitro. We identified HDAC4, PITX1 and ROBO1 that decreased bone metastatic ability after their simultaneous abrogation. These effects were solely linked to defects in osseous colonization. The molecular mechanisms related to bone colonization were mediated by non-cell autonomous effects that include the following: (1) a marked decrease in osteoclastogenic activity in vitro and in vivo, an effect associated with reduced pro-osteoclastogenic cytokines IL-11 and PTHrP expression levels, as well as decreased in vitro expression of stromal rankl in conditions mimicking tumor-stromal interactions; (2) an abrogated response to TGF-ß signaling by decreased phosphorylation and levels of Smad2/3 in tumor cells and (3) an impaired metalloproteolytic activity in vitro. Interestingly, coexpression of HDAC4 and PITX1 conferred high prometastatic activity in vivo. Further, levels of both genes correlated with patients at higher risk of metastasis in a clinical lung AC data set and with a poorer clinical outcome. These findings provide functional and clinical evidence that this metastatic subset is an important determinant of osseous colonization. These data suggest novel therapeutic targets to effectively block lung AC bone metastasis.

Topological study of the late steps of the artemisinin decomposition process: modeling the outcome of the experimentally obtained products.

By using 6,7,8-trioxabicyclo[3.2.2]nonane as the artemisinin model and dihydrated Fe(OH)(2) as the heme model, we report a theoretical study of the late steps of the artemisinin decomposition process. The study offers two viewpoints: first, the energetic and geometric parameters are obtained and analyzed, and hence, different reaction paths have been studied. The second point of view uses the electron localization function (ELF) and the atoms in molecules (AIM) methodology, to conduct a complete topological study of such steps. The MO analysis together with the spin density description has also been used. The obtained results agree nicely with the experimental data, and a new mechanistic proposal that explains the experimentally determined outcome of deoxiartemisinin has been postulated.

The role of solvent on the mechanism of proton transfer to hydride complexes: the case of the [W(3)PdS(4)H(3)(dmpe)(3)(CO)](+) cubane cluster.

The kinetics of reaction of the [W(3)PdS(4)H(3)(dmpe)(3)(CO)](+) hydride cluster (1(+)) with HCl has been measured in dichloromethane, and a second-order dependence with respect to the acid is found for the initial step. In the presence of added BF(4) (-) the second-order dependence is maintained, but there is a deceleration that becomes more evident as the acid concentration increases. DFT calculations indicate that these results can be rationalized on the basis of the mechanism previously proposed for the same reaction of the closely related [W(3)S(4)H(3)(dmpe)(3)](+) cluster, which involves parallel first- and second-order pathways in which the coordinated hydride interacts with one and two acid molecules, and ion pairing to BF(4) (-) hinders formation of dihydrogen bonded adducts able to evolve to the products of proton transfer. Additional DFT calculations are reported to understand the behavior of the cluster in neat acetonitrile and acetonitrile-water mixtures. The interaction of the HCl molecule with CH(3)CN is stronger than the W-H...HCl dihydrogen bond and so the reaction pathways operating in dichloromethane become inefficient, in agreement with the lack of reaction between 1(+) and HCl in neat acetonitrile. However, the attacking species in acetonitrile-water mixtures is the solvated proton, and DFT calculations indicate that the reaction can then go through pathways involving solvent attack to the W centers, while still maintaining the coordinated hydride, which is made possible by the capability of the cluster to undergo structural changes in its core.

A topological study of the decomposition of 6,7,8-trioxabicyclo[3.2.2]nonane induced by Fe(II): modeling the artemisinin reaction with heme.

We report a theoretical study on the electronic and topological aspects of the reaction of dihydrated Fe(OH)(2) with 6,7,8-trioxabicyclo[3.2.2]nonane, as a model for the reaction of heme with artemisinin. A comparison is made with the reaction of dihydrated ferrous hydroxide with O(2), as a model for the heme interaction with oxygen. We found that dihydrated Fe(OH)(2) reacts more efficiently with the artemisinin model than with O(2). This result suggests that artemisinin instead of molecular oxygen would interact with heme, disrupting its detoxification process by avoiding the initial heme to hemin oxidation, and killing in this way the malaria parasite. The ELF and AIM theories provide support for such a conclusion, which further clarifies our understanding on how artemisinin acts as an antimalarial agent.

Combined kinetic and DFT studies on the stabilization of the pyramidal form of H3PO2 at the heterometal site of [Mo3M'S4(H2O)10]4+ clusters (M' = Pd, Ni).

Kinetic and DFT studies have been carried out on the reaction of the [Mo(3)M'S(4)(H(2)O)(10)](4+) clusters (M' = Pd, Ni) with H(3)PO(2) to form the [Mo(3)M'(pyr-H(3)PO(2))S(4)(H(2)O)(9)](4+) complexes, in which the rare pyramidal form of H(3)PO(2) is stabilized by coordination to the M' site of the clusters. The reaction proceeds with biphasic kinetics, both steps showing a first order dependence with respect to H(3)PO(2). These results are interpreted in terms of a mechanism that involves an initial substitution step in which one tetrahedral H(3)PO(2) molecule coordinates to M' through the oxygen atom of the P=O bond, followed by a second step that consists in tautomerization of coordinated H(3)PO(2) assisted by a second H(3)PO(2) molecule. DFT studies have been carried out to obtain information on the details of both kinetic steps, the major finding being that the role of the additional H(3)PO(2) molecule in the second step consists in catalysing a hydrogen shift from phosphorus to oxygen in O-coordinated H(3)PO(2), which is made possible by its capability of accepting a proton from P-H to form H(4)PO(2)(+) and then transfer it to the oxygen. DFT studies have been also carried out on the reaction at the Mo centres to understand the reasons that make these metal centres ineffective for promoting tautomerization.

Unprecedented solvent-assisted reactivity of Hydrido W3CuS4 cubane clusters: the non-innocent behaviour of the cluster-core unit.

Opening the cluster core: Substitution of the chloride ligand in the novel cationic cluster [W(3)CuS(4)H(3)Cl(dmpe)(3)](+) (see figure; dmpe=1,2-bis(dimethylphosphino)ethane) by acetonitrile is promoted by water addition. Kinetic and density functional theory studies lead to a mechanistic proposal in which acetonitrile or water attack causes the opening of the cluster core with dissociation of one of the Cu--S bonds to accommodate the entering ligand.Reaction of the incomplete cuboidal cationic cluster [W(3)S(4)H(3)(dmpe)(3)](+) (dmpe=1,2-bis(dimethylphosphino)ethane) with Cu(I) compounds produces rare examples of cationic heterodimetallic hydrido clusters of formula [W(3)CuClS(4)H(3)(dmpe)(3)](+) ([1](+)) and [W(3)Cu(CH(3)CN)S(4)H(3)(dmpe)(3)](2+) ([2](2+)). An unexpected conversion of [1](+) into [2](2+), which involves substitution of chloride by CH(3)CN at the copper centre, has been observed in CH(3)CN/H(2)O mixtures. Surprisingly, formation of the acetonitrile complex does not occur in neat acetonitrile and requires the presence of water. The kinetics of this reaction has been studied and the results indicate that the process is accelerated when the water concentration increases and is retarded in the presence of added chloride. Computational studies have also been carried out and a mechanism for the substitution reaction is proposed in which attack at the copper centre by acetonitrile or water causes disruption of the cubane-type core. ESI-MS experiments support the formation of intermediates with an open-core cluster structure. This kind of process is unprecedented in the chemistry of M(3)M'Q(4) (M=Mo, W; Q=S, Se) clusters, and allows for the transient appearance of a new coordination site at the M' site which could explain some aspects of the reactivity and catalytic properties of this kind of clusters.

Catalytic effect of a second H3PO2 in the mechanism of stabilisation of the unstable pyramidal tautomer of H3PO2 coordinated at [Mo3S4M'] clusters (M' = Ni, Pd).

Kinetic and DFT studies indicate that the stabilization of a single pyramidal H(3)PO(2) molecule at the M' site of [Mo(3)S(4)M'] clusters requires the participation of two tetrahedral H(3)PO(2) molecules, the role of the second one being assisting tautomerization of a previously coordinated tetrahedral H(3)PO(2).

[Bone metastases]. / Las metástasis óseas del cáncer.

Bone metastases represent a devastating clinical problem in the most frequent neoplasies, especially in multiple myeloma, tumours breast, prostate and lung. The consequences include pain which is refractory to conventional analgesics, osteolysis often leading to bone-marrow compression and pathological fractures, and metabolic disorders. Recent advances in diagnosis using imaging techniques as well as different biochemical techniques have helped accurate diagnosis and follow-up. The increase in survival has improved through a multimodal approach combining, inhibition of osteolysis, with prophylactic orthopaedic surgery and radiation therapy. Recent advances in basic research have determined the molecular metastatic that can predict its proclivity to metastasize. Basic research will improve understanding of the basic mechanisms and lead to the clarification of molecular targets that will help in the development of medicines capable of preventing, decreasing or blocking the metastatic process.

Las metástasis óseas del cáncer / Bone metastases

Las metástasis óseas representan un problema clínicodevastador en las neoplasias más frecuentes,especialmente en el mieloma múltiple, mama, próstata,y pulmón. Las consecuencias incluyen dolores refractariosa analgésicos convencionales, osteolisis queconlleva en ocasiones compresión medular, fracturaspatológicas, y trastornos metabólicos. Recientes avancesen el diagnóstico mediante técnicas de imagen, asícomo diversas técnicas bioquímicas, han favorecidoun certero diagnóstico y seguimiento. El aumento de lasupervivencia se ha mejorado mediante una aproximaciónmultimodal en los tratamientos con la combinaciónde la inhibición de la osteolisis, la cirugía ortopédicaprofiláctica y la radioterapia. Recientes progresosen la investigación básica han determinado la huellamolecular de metástasis de un tumor capaz de predecirsu proclividad metastásica. La investigación básicafavorecerá un conocimiento de los mecanismos básicosy llevará a elucidar dianas moleculares que favoreceránel desarrollo de fármacos capaces de prevenir,amortiguar o bloquear el proceso metastático

Bone metastases represent a devastating clinical ;;problem in the most frequent neoplasies, especially ;;in multiple myeloma, tumours breast, prostate ;;and lung. The consequences include pain which is ;;refractory to conventional analgesics, osteolysis ;;often leading to bone-marrow compression and ;;pathological fractures, and metabolic disorders. ;;Recent advances in diagnosis using imaging techniques ;;as well as different biochemical techniques ;;have helped accurate diagnosis and follow-up. The ;;increase in survival has improved through a multimodal ;;approach combining, inhibition of osteolysis, ;;with prophylactic orthopaedic surgery and radiation ;;therapy. Recent advances in basic research have ;;determined the molecular metastatic that can predict ;;its proclivity to metastasize. Basic research will ;;improve understanding of the basic mechanisms and ;;lead to the clarification of molecular targets that will ;;help in the development of medicines capable of preventing, ;;decreasing or blocking the metastatic ;;process

The structure of ([W3Q4X3(dmpe)3]+, Y-) ion pairs (Q = S, Se; X = H, OH, Br; Y = BF4, PF6, dmpe = Me2PCH2CH2PMe2) in dichloromethane solution and the effect of ion-pairing on the kinetics of proton transfer to the hydride cluster [W3S4H3(dmpe)3]+.

The 1H,19F HOESY spectra of the title compounds in CD2Cl2 solution indicate that the cluster cations form ion pairs with the BF4- and PF6- anions with a well-defined interionic structure that appears to be basically determined essentially by the nature of the X- ligand. For the clusters with X = H and OH, the structure of the ion pairs is such that the counteranion (Y-) and the X- ligands are placed close to each other. However, when the size and electron density of X- increase (X = Br), Y- is forced to move to a different site, far away from X-. The relevance of ion-pairing on the chemistry of these compounds is clearly seen through a decrease in the rate of proton transfer from HCl to the hydride cluster [W3S4H3(dmpe)3]+ in the presence of an excess of BF4-. The kinetic data for this reaction can be rationalized by considering that the ([W3S4H3(dmpe)3]+, BF4-) ion pairs are unproductive in the proton-transfer process. Theoretical calculations indicate that the real behavior can be more complex. Although the cluster can still form adducts with HCl in the presence of BF4-, the structures of the most-stable BF4--containing HCl adducts show H...H distances too large to allow the subsequent release of H2. In addition, the effective concentration of HCl is also reduced because of the formation of adducts as ClH...BF4-. As a consequence of both effects, the proton transfer takes place more slowly than for the case of the dihydrogen-bonded HCl adduct resulting from the unpaired cluster.

Modeling the decomposition mechanism of artemisinin.

A theoretical study on artemisinin decomposition mechanisms is reported. The calculations have been done at the HF/3-21G and B3LYP/6-31G(d,p) theoretical levels, by using 6,7,8-trioxybicyclo[3.2.2]nonane as the molecular model for artemisinin, and a hydrogen atom, modeling the single electron transfer from heme or Fe(II) in the highly acidic parasite's food vacuole, as inductor of the initial peroxide bond cleavage. All relevant stationary points have been characterized, and the appearance of the final products can be explained in a satisfactory way. Several intermediates and radicals have been found as relatively stable species, thus giving support to the current hypothesis that some of these species can be responsible for the antimalarial action of artemisinin and its derivatives.

New insights into the mechanism of proton transfer to hydride complexes: kinetic and theoretical evidence showing the existence of competitive pathways for protonation of the cluster [W3S4H3(dmpe)3]+ with acids.

The reaction of the hydride cluster [W3S4H3(dmpe)3]+ (1, dmpe = 1,2-bis(dimethylphosphanyl)ethane) with acids (HCl, CF3COOH, HBF4) in CH2Cl2 solution under pseudo-first-order conditions of excess acid occurs with three kinetically distinguishable steps that can be interpreted as corresponding to successive formal substitution processes of the coordinated hydrides by the anion of the acid (HCl, CF3COOH) or the solvent (HBF4). Whereas the rate law for the third step changes with the nature of the acid, the first two kinetic steps always show a second-order dependence on acid concentration. In contrast, a single kinetic step with a first-order dependence with respect to the acid is observed when the experiments are carried out with a deficit of acid. The decrease in the T1 values for the hydride NMR signal of 1 in the presence of added HCl suggests the formation of an adduct with a W-H...H-Cl dihydrogen bond. Theoretical calculations for the reaction with HCl indicate that the kinetic results in CH2Cl2 solution can be interpreted on the basis of a mechanism with two competitive pathways. One of the pathways consists of direct proton transfer within the W-H...H-Cl adduct to form W-Cl and H2, whereas the other requires the presence of a second HCl molecule to form a W-H...H-Cl...H-Cl adduct that transforms into W-Cl, H2 and HCl in the rate-determining step. The activation barriers and the structures of the transition states for both pathways were also calculated, and the results indicate that both pathways can be competitive and that the transition states can be described in both cases as a dihydrogen complex hydrogen-bonded to Cl- or HCl2(-).