Study of the ability of carboranylcarboxylate ligands to generate polynuclear compounds. Potential applications

In this thesis is presented the synthesis and characterization of two different carboranylcarboxylate ligands, 1-CH3-2-CO2H-1,2-closo-C2B10H10 and 1-CO2H-1,2-closo-C2B10H11, in which the methyl group bonded to the carbon of the carborane cluster was replaced by a hydrogen atom. The coordination chemistry of the two ligands towards different transition metals (Cu(II), Mn(II), Fe(II) and Co(II)) has been studied and compared, affording a series of mono- and binuclear complexes which have been fully characterized and their main physical and chemical properties have been studied experimental and theoretically. It has also been paid attention to the magnetic behaviour of the binuclear complexes containing the ligand 1-CH3-2-CO2H-1,2-closo-C2B10H10 and the copper(II) and manganese(II) ions, these findings have been corroborated by electronic-structure calculations. Finally, it has been studied the catalytic activity of some of the manganese(II) and cobalt((II) complexes with regard to the epoxidation of alkenes and the water oxidation.En aquesta tesis es presenta la síntesi i caracterització de dos lligands diferents de tipus carboranilcarboxilat l’ 1-CH3-2-CO2H-1,2-closo-C2B10H10 i l’ 1-CO2H-1,2-closo-C2B10H11, en el qual el grup metil unit al clúster del carborà es substituït per un àtom d’hidrogen. S’ha estudiat i comparat la química de coordinació dels dos lligands amb diferents metalls de transició (Cu(II), Mn(II), Fe(II) i Co(II)) que condueix a una sèrie de complexos mono- i polinuclears els quals han estat caracteritzats exhaustivament mitjançant diferents tècniques de caracterització; tanmateix, les seves principals propietats físiques i químiques han sigut estudiades experimental i teòricament. També s’ha incidit en l’estudi del comportament magnètic dels complexos binuclears amb el lligand 1-CH3-2-CO2H-1,2-closo-C2B10H10, i els ions coure(II) i manganès(II), els resultats dels quals van ser corroborats mitjançant estudis teòrics. Finalment, es va avaluar l’activitat catalítica d’alguns dels complexos de manganès(II) i cobalt(II) respecte les reaccions d’epoxidació d’alquens i oxidació d’aigua

Carboranycarboxylate Complexes as Efficient Catalysts in Epoxidation Reactions

This work presents the first examples of carboranylcarboxylate complexes as precatalysts in epoxidation reactions with the use of peracetic acid as the oxidant. The manganese [Mn(μ-H2O)(1-CH3-2-CO2-1,2-closo-C2B10H10)2]n·(H2O)n (1), [Mn2(1-CH3-2-CO2-1,2-closo-C2B10H10)4(2,2'-bpy)2] (2, bpy = bipyridine), [Mn(1-CH3-2-CO2-1,2-closo-C2B10H10)2(bpm)]n (3, bpm = bipyrimidine), and [Mn(1-CH3-2-CO2-1,2-closo-C2B10H10)2(2,2'-bpy)2] (4) complexes and the cobalt [Co2(μ-H2O)(1-CH3-2-CO2-1,2-closo-C2B10H10)4(thf)4] (6) complex, all containing the carboranylcarboxylic 1-CH3-2-CO2H-1,2-closo-C2B10H10 (LH) ligand, together with Mn3(OAc)6(2,2'-bpy)2 (5) displayed good performance with high conversions and selectivity values in short reaction times, in most cases. This work highlights that the coordination of the carboranylcarboxylic ligand to the metal ions is crucial to the performance of the complexes as catalystsThis research has been financed by the Spanish Ministerio de Economía y Competitividad (CTQ2015-66143-P; CTQ2016-75150-R) and Generalitat de Catalunya through project 2014-SGR-14

Carving 1D CoII-carboranylcarboxylate system by organic solvents creating stable trinuclear molecular analogous: complete structural and magnetic studies

This work presents a straightforward methodology to achieve small linear trinuclear molecules based on the CoII-carboranylcarboxylate system obtained by carving a 1D polynuclear analogous system with the use of diethylether. The reaction of the carboranylcarboxylic ligand, 1-CH3-2-CO2H-1,2-closo-C2B10H10 (LH) with different cobalt salts leads to the polynuclear compound [Co2(μ-H2O)(1-CH3-2-CO2-1,2-closo- C2B10H10)4(THF)4], 1 and the polymeric [Co(μ-H2O)(1-CH3-2-CO2-1,2-closo-C2B10H10)2]n(H2O)n 2. This latter 1D chain has been obtained by an unprecedented synthetic strategy for the isolation of cobalt(II) compounds.[Co3(μ-H2O)2(1-CH3-2-CO2-1,2-closo-C2B10H10)6(H2O)2(C4H10O)2], 3 is formed by the dissociation of the polymeric structure that forms 2 when a mild coordinating solvent such as diethylether is added. These compounds have been characterized by analytical and spectroscopic techniques. X-ray analysis of 1 and 3 revealed that 1 presents a dinuclear structure whereas 3 is trinuclear; in both cases a six-coordinated CoII compound with water molecules bridging each of the two CoII centres has been observed. The magnetic properties of 1 and 3 show a weak antiferromagnetic behaviour, respectively, between the CoII centres mediated by two carboxylate ligands and a molecule of wate

Evidence supporting regulatory-decision making on orphan medicinal products authorisation in Europe : methodological uncertainties

To assess uncertainty in regulatory decision-making for orphan medicinal products (OMP), a summary of the current basis for approval is required; a systematic grouping of medical conditions may be useful in summarizing information and issuing recommendations for practice. A grouping of medical conditions with similar characteristics regarding the potential applicability of methods and designs was created using a consensus approach. The 125 dossiers for authorised OMP published between 1999 and 2014 on the EMA webpage were grouped accordingly and data was extracted from European Public Assessment Reports (EPARs) to assess the extent and robustness of the pivotal evidence supporting regulatory decisions. 88% (110/125) of OMP authorizations were based on clinical trials, with 35% (38/110) including replicated pivotal trials. The mean (SD) number of pivotal trials per indication was 1.4 (0.7), and the EPARs included a median of three additional non-pivotal supportive studies. 10% of OMPs (13/125) were authorised despite only negative pivotal trials. One-third of trials (53/159) did not include a control arm, one-third (50/159) did not use randomisation, half the trials (75/159) were open-label and 75% (119/159) used intermediate or surrogate variables as the main outcome. Chronic progressive conditions led by multiple system/organs, conditions with single acute episodes and progressive conditions led by one organ/system were the groups where the evidence deviated most from conventional standards. Conditions with recurrent acute episodes had the most robust datasets. The overall size of the exposed population at the time of authorisation of OMP − mean(SD) 190.5 (202.5) − was lower than that required for the qualification of clinically-relevant adverse reactions. The regulatory evidence supporting OMP authorization showed substantial uncertainties, including weak protection against errors, substantial use of designs unsuited for conclusions on causality, use of intermediate variables, lack of a priorism and insufficient safety data to quantify risks of relevant magnitude. Grouping medical conditions based on clinical features and their methodological requirements may facilitate specific methodological and regulatory recommendations for the study of OMP to strengthen the evidence base. The online version of this article (10.1186/s13023-018-0926-z) contains supplementary material, which is available to authorized users

Evidence supporting regulatory-decision making on orphan medicinal products authorisation in Europe : methodological uncertainties

BACKGROUND: To assess uncertainty in regulatory decision-making for orphan medicinal products (OMP), a summary of the current basis for approval is required; a systematic grouping of medical conditions may be useful in summarizing information and issuing recommendations for practice. METHODS: A grouping of medical conditions with similar characteristics regarding the potential applicability of methods and designs was created using a consensus approach. The 125 dossiers for authorised OMP published between 1999 and 2014 on the EMA webpage were grouped accordingly and data was extracted from European Public Assessment Reports (EPARs) to assess the extent and robustness of the pivotal evidence supporting regulatory decisions. RESULTS: 88% (110/125) of OMP authorizations were based on clinical trials, with 35% (38/110) including replicated pivotal trials. The mean (SD) number of pivotal trials per indication was 1.4 (0.7), and the EPARs included a median of three additional non-pivotal supportive studies. 10% of OMPs (13/125) were authorised despite only negative pivotal trials. One-third of trials (53/159) did not include a control arm, one-third (50/159) did not use randomisation, half the trials (75/159) were open-label and 75% (119/159) used intermediate or surrogate variables as the main outcome. Chronic progressive conditions led by multiple system/organs, conditions with single acute episodes and progressive conditions led by one organ/system were the groups where the evidence deviated most from conventional standards. Conditions with recurrent acute episodes had the most robust datasets. The overall size of the exposed population at the time of authorisation of OMP - mean(SD) 190.5 (202.5) - was lower than that required for the qualification of clinically-relevant adverse reactions. CONCLUSIONS: The regulatory evidence supporting OMP authorization showed substantial uncertainties, including weak protection against errors, substantial use of designs unsuited for conclusions on causality, use of intermediate variables, lack of a priorism and insufficient safety data to quantify risks of relevant magnitude. Grouping medical conditions based on clinical features and their methodological requirements may facilitate specific methodological and regulatory recommendations for the study of OMP to strengthen the evidence base