Catalytic Hydrogenation of Azobenzene in the Presence of a Cuboidal Mo3S4 Cluster via an Uncommon Sulfur-Based H2 Activation Mechanism

Azobenzene hydrogenation is catalyzed under moderate conditions by a cuboidal Mo3(μ3-S)(μ-S)3 diamino complex via a cluster catalysis mechanism. Dihydrogen activation by the molecular [Mo3(μ3-S)(μ-S)3Cl3(dmen)3]+ cluster cation takes place at the μ-S bridging atoms without direct participation of the metals in clear contrast with classical concepts. The reaction occurs with the formation of 1,2-diphenylhydrazine as an intermediate with similar appearance and disappearance rate constants. On the basis of DFT calculations, a mechanism is proposed in which formation of 1,2-diphenylhydrazine and aniline occurs through two interconnected catalytic cycles that share a common reaction step that involves H2 addition to two of the bridging sulfur atoms of the catalyst to form a dithiolate Mo3(μ3-S)(μ-SH)2)(μ-S) adduct. Both catalytic cycles have similar activation barriers, in agreement with the experimental observation of close rate constant values. Microkinetic modeling of the process leads to computed concentration–time profiles in excellent agreement with the experimental ones providing additional support to the calculated reaction mechanism. Slight modifications on the experimental conditions of the catalytic protocol in combination with theoretical calculations discard a direct participation of the metal on the reaction mechanism. The effect of the ancillary ligands on the catalytic activity of the cluster fully agrees with the present mechanistic proposal. The results herein demonstrate the capability of molybdenum sulfide materials to activate hydrogen through an uncommon sulfur based mechanism opening attractive possibilities toward their applications as catalysts in other hydrogenation processes

Benchmarking of DFTmethods using experimental free energies and volumes of activation for the cycloaddition of alkynes to cuboidalMo(3)S(4)clusters

Here, the kinetics of the concerted [3 + 2] cycloaddition reaction between the [Mo3(μ3‐S)(μ‐S)3Cl3(dmen)3]+ (dmen = N,N′‐dimethyl‐ethylenediamine) ([1]+) cluster and various alkynes to form dithiolene derivatives is thoroughly studied, with measurements at different temperatures and pressures allowing the determination of the free energies and volumes of activation. These parameters, together with the available single‐crystal X‐ray diffraction structures, are used to test a number of commonly used density functional theory (DFT) methods from Jacob's ladder, as well as the effects associated with the size of the basis sets, the way in which solvent effects are taken into account, or the inclusion of dispersion effects. Overall, a protocol that leads to average deviations between experimental and computed ΔV‡ and ΔG‡ values similar to the uncertainty of the experimental measurements is obtained

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 β-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.Funding for open access charge: CRUE-Universitat Jaume

Benchmarking of DFT methods using experimental free energies and volumes of activation for the cycloaddition of alkynes to cuboidal Mo3S4 clusters

Here, the kinetics of the concerted [3 + 2] cycloaddition reaction between the [Mo3(μ3‐S)(μ‐S)3Cl3(dmen)3]+ (dmen = N,N′‐dimethyl‐ethylenediamine) ([1]+) cluster and various alkynes to form dithiolene derivatives is thoroughly studied, with measurements at different temperatures and pressures allowing the determination of the free energies and volumes of activation. These parameters, together with the available single‐crystal X‐ray diffraction structures, are used to test a number of commonly used density functional theory (DFT) methods from Jacob's ladder, as well as the effects associated with the size of the basis sets, the way in which solvent effects are taken into account, or the inclusion of dispersion effects. Overall, a protocol that leads to average deviations between experimental and computed ΔV and ΔG values similar to the uncertainty of the experimental measurements is obtained

Efficient (Z)-selective semihydrogenation of alkynes catalyzed by air-stable imidazolyl amino molybdenum cluster sulfides

Imidazolyl amino cuboidal Mo3(μ3-S)(μ-S)3 clusters have been investigated as catalysts for the semihydrogenation of alkynes. For that purpose, three new air-stable cluster salts [Mo3S4Cl3(ImNH2)3]BF4 ([1]BF4), [Mo3S4Cl3(ImNH(CH3))3]BF4 ([2]BF4) and [Mo3S4Cl3(ImN(CH3)2)3]BF4 ([3]BF4) have been isolated in moderate to high yields and fully characterized. Crystal structures of complexes [1]PF6 and [2]Cl confirm the formation of a single isomer in which the nitrogen atoms of the three imidazolyl groups of the ligands are located trans to the capping sulfur atom which leaves the three bridging sulfur centers on one side of the trimetallic plane while the amino groups lie on the opposite side. Kinetic studies show that the cluster bridging sulfurs react with diphenylacetylene (dpa) in a reversible equilibrium to form the corresponding dithiolene adduct. Formation of this adduct is postulated as the first step in the catalytic semihydrogenation of alkynes mediated by molybdenum sulfides. These complexes catalyze the (Z)-selective semihydrogenation of diphenylacetylene (dpa) under hydrogen in the absence of any additives. The catalytic activity lowers sequentially upon replacement of the hydrogen atoms of the N–H2 moiety in 1+ without reaching inhibition. Mechanistic experiments support a sulfur centered mechanism without participation of the amino groups. Different diphenylacetylene derivatives are selectively hydrogenated using complex 1+ to their corresponding Z-alkenes in excellent yields. Extension of this protocol to 3,7,11,15-tetramethylhexadec-1-yn-3-ol, an essential intermediate for the production of vitamin E, affords the semihydrogenation product in very good yield

Cycloaddition of alkynes to diimino Mo3S4 cubane-type clusters: a combined experimental and theoretical approach

A heterocyclic ligand 4,40-di-tert-butyl-2,20-bipyridine (dbbpy) has been coordinated to the Mo3S4 cluster unit affording the complex [Mo3S4Cl3(dbbpy)3]+ ([1]+) in a one-step ligand-exchange protocol from [Mo3S4(tu)8(H2O)]Cl4 4H2O (tu = thiourea). The new cluster was isolated as [1]PF6 and [1]Cl salts in high yields and the crystal structure of the latter determined by X-ray analysis. The synthetic procedure was extended to tungsten to afford [W3S4Cl3(dbbpy)3]+ ([2]+). Kinetic and NMR studies show that [1]+ reacts with several alkynes to form dithiolene species via concerted [3+2] cycloaddition reactions whereas [2]+ remains inert under similar conditions. The different rates for the reactions of [1]+ are rationalised by computational (DFT) calculations, which show that the more electron-withdrawing the substituents of the alkyne the faster the reaction. The inertness of [2]+ is due to the endergonicity of its reactions, which feature DGr values systematically 5–7 kcal mol 1 more positive than for those of [1]+

Bifunctional W/NH Cuboidal Aminophosphino W3S4 Cluster Hydrides: The Puzzling Behaviour behind the Hydridic-Protonic Interplay

The novel [W3S4H3(edpp)3]+ (edpp=(2-aminoethyl)diphenylphosphine) (1+) cluster hydride with an acidic −NH2 functionality has been synthetized and studied. Its crystal structure shows the characteristic incomplete W3S4 cubane core with the outer positions occupied by the P and N atoms of the edpp ligands. Although no signal due to the hydride ligands is observed in the 1H NMR spectrum, hydride assignment is supported by 1H-15N HSQC techniques, the changes in the 31P{1H} NMR chemical shift, and FT-IR spectra in the W−H region of the deuterated [W3S4D2H(edpp)3]+ (1+-d2) samples. Moreover, all NMR evidences suggest that one of the hydrogen atoms of the NH2 group in 1+ is rapidly exchanging with the hydride. The reaction of 1+ with acids (HCl, HBr and DCl) features complex polyphasic kinetics with zero-order dependence with respect to the acid concentration, being also independent of the solvent nature. This behavior differs from that of their diphosphino analogues, suggesting a different mechanism

Long-Term Outcomes After Autologous Versus Allogeneic Stem Cell Transplantation in Molecularly-Stratified Patients With Intermediate Cytogenetic Risk Acute Myeloid Leukemia: A PETHEMA Study

PETHEMA (Programa Español de Tratamientos en Hematología) and GETH (Grupo Espa~nol de Trasplante Hematopoyético y Terapia Celular) Cooperative GroupsAcute myeloid leukemia (AML) with intermediate risk cytogenetics (IRcyto) comprises a variety of biological entities with distinct mutational landscapes that translate into differential risks of relapse and prognosis. Optimal postremission therapy choice in this heterogeneous patient population is currently unsettled. In the current study, we compared outcomes in IRcyto AML recipients of autologous (autoSCT) (n = 312) or allogeneic stem cell transplantation (alloSCT) (n = 279) in first complete remission (CR1). Molecular risk was defined based on CEBPA, NPM1, and FLT3-ITD mutational status, per European LeukemiaNet 2017 criteria. Five-year overall survival (OS) in patients with favorable molecular risk (FRmol) was 62% (95% confidence interval [CI], 50-72) after autoSCT and 66% (95% CI, 41-83) after matched sibling donor (MSD) alloSCT (P = .68). For patients of intermediate molecular risk (IRmol), MSD alloSCT was associated with lower cumulative incidence of relapse (P < .001), as well as with increased nonrelapse mortality (P = .01), as compared to autoSCT. The 5-year OS was 47% (95% CI, 34-58) after autoSCT and 70% (95% CI, 59-79) after MSD alloSCT (P = .02) in this patient subgroup. In a propensity-score matched IRmol subcohort (n = 106), MSD alloSCT was associated with superior leukemia-free survival (hazard ratio [HR] 0.33, P = .004) and increased OS in patients alive 1 year after transplantation (HR 0.20, P = .004). These results indicate that, within IRcyto AML in CR1, autoSCT may be a valid option for FRmol patients, whereas MSD alloSCT should be the preferred postremission strategy in IRmol patients.Supported by a Río Hortega academic clinical fellowship (CM19/00194) from the Instituto de Salud Carlos III, Spain (E.R.A.). Additional funding has been provided by CIBERONC grants to J.P.S. (CB16/12/00480), M.M.S. (CB16/12/00369) and B.V. (CB16/12/00233)

Prognostic significance of FLT3-ITD length in AML patients treated with intensive regimens

FLT3-ITD mutations are detected in approximately 25% of newly diagnosed adult acute myeloid leukemia (AML) patients and confer an adverse prognosis. The FLT3-ITD allelic ratio has clear prognostic value. Nevertheless, there are numerous manuscripts with contradictory results regarding the prognostic relevance of the length and insertion site (IS) of the FLT3-ITD fragment. We aimed to assess the prognostic impact of these variables on the complete remission (CR) rates, overall survival (OS) and relapse-free survival (RFS) of AML patients with FLT3-ITDmutations. We studied the FLT3-ITD length of 362 adult AML patients included in the PETHEMA AML registry. We tried to validate the thresholds of ITD length previously published (i.e., 39 bp and 70 bp) in intensively treated AML patients (n = 161). We also analyzed the mutational profile of 118 FLT3-ITD AML patients with an NGS panel of 39 genes and correlated mutational status with the length and IS of ITD. The AUC of the ROC curve of the ITD length for OS prediction was 0.504, and no differences were found when applying any of the thresholds for OS, RFS or CR rate. Only four out of 106 patients had ITD IS in the TKD1 domain. Our results, alongside previous publications, confirm that FLT3-ITD length lacks prognostic value and clinical applicability. © 2021, The Author(s)

Outcomes and prognostic factors of adults with refractory or relapsed T-cell acute lymphoblastic leukemia included in measurable residual disease-oriented trials

Despite high complete remission (CR) rates with frontline therapy, relapses are frequent in adults with T-cell acute lymphoblastic leukemia (T-ALL) with limited salvage options. We analyzed the outcomes and prognostic factors for CR to salvage therapy and overall survival (OS) of patients with R/R T-ALL included in two prospective measurable residual disease-oriented trials. Seventy-five patients (70 relapsed, 5 refractory) were identified. Relapses occurred in bone marrow, isolated or combined in 50 patients, and in the central nervous system (CNS; isolated or combined) in 20. Second CR was attained in 30/75 patients (40%). Treatment with FLAG-Ida and isolated CNS relapse were independently associated with a higher CR rate after first salvage therapy. The median OS was 6.2 (95% confidence interval [CI], 3.9–8.6) months, with a 4-year OS probability of 18% (95% CI, 9%–27%). No differences in survival were observed according to the treatment with hematopoietic stem cell transplantation in patients in CR after first salvage therapy. Multivariable analysis showed a ≥12-month interval between first CR and relapse, CR after first salvage therapy and isolated CNS relapse as favorable prognostic factors for OS with hazard ratios (HR) (95% CI) of 1.931 (1.109–3.362), 2.958 (1.640–5.334), and 2.976 (1.157–7.655), respectively. This study confirms the poor outcomes of adults with R/R T-ALL among whom FLAG-Ida was the best of the rescue therapies evaluated. Late relapse, CR after first rescue therapy and isolated CNS relapse showed prognostic impact on survival. More effective rescue therapies are needed in adults with R/R T-ALL.La Caixa" Foundation and ISCIII, Grant/ Award Number: PI19/01828; Generalitat de Catalunya (GRC), Grant/Award Number: 2017 SGR28