Pyrazolone-based metal complexes: synthesis, characterization and theoretical study of Zn(II), Cu(II) and Mo(IV) derivatives

4-acyl-5-pyrazolones are a class of compounds that combine the properties of the pyrazolone ring with that of diketones, affording an O,O-chelating ligand with biological features. Since the first synthesis by Jensen in 1959 they have been the subject of a multitude of studies concerning their tautomeric forms, their biological properties, and their coordination chemistry towards a variety of metal centres. Furthermore, the readiness of the structural modifications they can undergo pushed researchers to explore many different variations tailoring the substituents to optimize their coordination with the metals and to vary their properties. In particular, one interesting variant of 4-acyl-5-pyrazolones is obtained by condensation with hydrazine or amine to afford N,O-chelating Schiff base ligands. This class of ligands retains all the characteristics of their synthon and additionally, they show enhanced coordination features due to the presence of one or more nitrogen atoms. In Chapter 1 an introduction to these compounds is reported together with a comprehensive state-of-the-art of their metal complexes, involving zinc, copper, and molybdenum. Chapter 2 deals with the synthesis and characterization of Schiff base ligands and the study of their tautomerism in solid state and solution. The ligands have then been utilized to synthesize the respective zinc(II) complexes of composition [Zn(HLn )2], they were fully characterized and the structures of two ligands and three complexes were determined by X-ray diffraction, showing that complexes 1 and 2 have a monomeric nature, while complex 4 exists as one-dimensional coordination polymer. DFT calculations on proligands, anions and complexes were exploited to confirm the experimental result and rationalized the polymeric nature of complex 4 and the presence of two water molecules coordinated on complexes 3 and 5. The antimicrobial activity of the compounds was investigated against Escherichia coli and Staphylococcus aureus. Complexes 4 and 5 demonstrated good efficiency, the latter probably for its ligand containing aliphatic and fluorinated substituents. Similarly, in Chapter 3 two hydrazone ligands were synthesized, characterized and reacted with Zn(II) and Cu(II) affording four complexes of formula [Zn(HL1 )2(MeOH)2], [Cu(HL1 )2], and [M(HL2 )2]. DFT and XRD studies determined that the free proligands exist in the NH,NH tautomeric form, [Zn(HL1 )2(MeOH)2] has an octahedral geometry with two apical methanol molecules, [Cu(HL1 )2] adopts a square planar geometry, and the two [M(HL2 )2] are octahedral with the ligands acting as tridentate O,N,N-donors in planar conformation. All the compounds were tested against the parasite Trypanosoma brucei and Balb3T3 cells obtaining powerful results, from the ligand H2L 1 and its Zn complex, showing a high selectivity index. For this reason, the mechanism of action of these two compounds has been investigated, indicating a strong impact on the CTP (cytidine triphosphate) pools, making it likely that CTP synthetase is the targeted enzyme. Chapter 4 is focused on the theoretical study of the mechanism of molybdenum-catalyzed deoxydehydration (DODH) of vicinal diols to alkenes. The mechanism has been investigated employing DFT calculations and considering [Mo(O)2(QMe)2] as a catalyst, where QMe is an O,O-donor pyrazolone-based ligand, and PMe3 as a reductant. Two different pathways have been analysed differing in the order of the main steps of the reaction. The lowest energy profiles were calculated for both, and the data obtained suggest that the second pathway is energetically preferred. Finally, In Chapter 5, a list of activities aimed at improving the efficiency of the processes of TechPol srl, a company active in the field of technopolymer molding, is reported. The activities carried out have optimized the use of recycled materials in a circular economy perspective, investigating the nature of the problems encountered and confirming that the main cause was the material used

Laura Olivieri,a Claudio Pettinari, b Duane Choquesillo-Lazarte, c Amalia García-García,d Antonio Rodríguez-Diéguez d and Agustín Galindo

Hydrazones and their metal derivatives are very important compounds in medicinal chemistry due to their reported variety of biological activities, such as antibacterial, antifungal and anticancer action. Five hydrazone-pyrazolone ligands HL (n = 1-5) were prepared and fully characterized and their tautomerism was investigated in the solid state and solution. Five zinc(ii) complexes 1-5 of composition [Zn(HL)] (n = 1 and 2), [Zn(HL)(HO)] (n = 3 and 5) and [Zn(HL)] were synthesized and characterized by elemental analysis, IR, H, F, C, and N NMR spectroscopy, and ESI mass spectrometry. In addition, the structures of two ligands and three complexes were determined by single-crystal X-ray diffraction. The ligands HL and HL exist both in the NH,NH tautomeric form. Complexes 1 and 2 are mononuclear compounds, while complex 4 is a one-dimensional coordination compound. Density functional theory (DFT) calculations were carried out on proligands, their anions and all zinc complexes, confirming the experimental results, supporting IR and NMR assignments and giving proofs of the mononuclear diaqua structure of complexes 3 and 5. The antibacterial activity of the free ligands and the Zn(ii) complexes was established against Escherichia coli and Staphylococcus aureus, and a strong efficiency has been found for Zn(ii) complexes, particularly for the polynuclear 4 and the mononuclear diaqua complex 5, the latter containing a ligand with aliphatic and fluorinated substituents able to compromise the permeability of and disrupt the bacterial cell membrane.Thanks are due to the University of Camerino (Italy) for financial support. The research grant of Dr Laura Olivieri was funded under the frame of the project Nano4-Fresh – Nanomaterials for an environmentally friendly and sustainable handling of perishable products (PRIMA19_00246), which is part of the Partnership on Research and Innovation in the Mediterranean Area (PRIMA) Programme supported by the European Union and funded by the national funding bodies of Participating States (MUR in Italy is gratefully acknowledged). We thank the Marche Region for supporting this research by funding the two-year research grant of Dr Sonila Xhafa as part of the POR Marche FSE 2014–2020 P.I. 8.1 R.A. 8.5. Financial support from the Spanish Ministerio de Ciencia e Innovación (PGC2018-093443-B-I00) is gratefully acknowledged

Theoretical studies on the mechanism of molybdenum-catalysed deoxydehydration of diols

Molybdenum-catalysed deoxydehydration (DODH) of vicinal diols to alkenes has been investigated using density functional theory (DFT). In particular, the mechanism of DODH of diols using a phosphane as a reductant and a [Mo(O)2(QR)2] complex (QR = acylpyrazolonate ligand) as a catalyst has been studied. This reaction was the first description of a Mo-catalysed DODH reaction. Two alternative routes, A and B, have been analysed in which the commonly recognised key steps in DODH processes have been considered: (i) activation of the diol by condensation and formation of a Mo-diolate intermediate, (ii) oxygen atom transfer to phosphane with reduction to a Mo(IV) species, and (iii) alkene extrusion from the Mo-diolate with regeneration of the starting dioxidomolybdenum(VI) complex. In pathway A, the activation of the diol by the molybdenum complex occurred before the oxygen atom transfer, while in pathway B, the oxygen atom transfer of the dioxidomolybdenum complex to the phosphane occurred before the diol activation. In both routes, the final step was alkene extrusion from the molybdenum-diolate species. Pathway B, in which the reduction by phosphane preceded the diol condensation, is energetically preferred to pathway A.Ministerio de Ciencia, Innovación y Universidades de España - PGC2018-093443-B-I0

Role of hydrazone substituents in determining the nuclearity and antibacterial activity of Zn(II) complexes with pyrazolone-based hydrazones

Hydrazones and their metal derivatives are very important compounds in medicinal chemistry due to their reported variety of biological activities, such as antibacterial, antifungal and anticancer action. Five hydrazone-pyrazolone ligands H2Ln (n = 1–5) were prepared and fully characterized and their tautomerism was investigated in the solid state and solution. Five zinc(II) complexes 1–5 of composition [Zn(HLn )2] (n = 1 and 2), [Zn(HLn )2(H2O)2] (n = 3 and 5) and [Zn(HL4 )2]n were synthesized and characterized by elemental analysis, IR, 1 H, 19F, 13C, and 15N NMR spectroscopy, and ESI mass spectrometry. In addition, the structures of two ligands and three complexes were determined by single-crystal X-ray diffraction. The ligands H2L2 and H2L4 exist both in the NH,NH tautomeric form. Complexes 1 and 2 are mononuclear compounds, while complex 4 is a one-dimensional coordination compound. Density functional theory (DFT) calculations were carried out on proligands, their anions and all zinc complexes, confirming the experimental results, supporting IR and NMR assignments and giving proofs of the mononuclear diaqua structure of complexes 3 and 5. The antibacterial activity of the free ligands and the Zn(II) complexes was established against Escherichia coli and Staphylococcus aureus, and a strong efficiency has been found for Zn(II) complexes, particularly for the polynuclear 4 and the mononuclear diaqua complex 5, the latter containing a ligand with aliphatic and fluorinated substituents able to compromise the permeability of and disrupt the bacterial cell membrane.Ministerio de Ciencia e Innovación de España - PGC2018-093443-B-I0

Zinc(II) Complex with Pyrazolone-Based Hydrazones is Strongly Effective against Trypanosoma brucei Which Causes African Sleeping Sickness

Two pyrazolone-based hydrazones H2L′ [in general, H2L′ in detail, H2L1 = 5-methyl-2-phenyl-4-(2-phenyl-1-(2-(4-(trifluoromethyl)phenyl)hydrazineyl)ethyl)-2,4-dihydro-3H-pyrazol-3-one, H2L2 = (Z)-5-methyl-2-phenyl-4-(2-phenyl-1-(2-(pyridin-2-yl)hydrazineyl)ethylidene)-2,4-dihydro-3H-pyrazol-3-one] were reacted with Zn(II) and Cu(II) acceptors affording the complexes [Zn(HL1)2(MeOH)2], [Cu(HL1)2], and [M(HL2)2] (M = Cu or Zn). X-ray and DFT studies showed the free proligands to exist in the N-H,N-H tautomeric form and that in [Zn(HL1)2(MeOH)2], zinc is six-coordinated by the N,O-chelated (HL1) ligand and other two oxygen atoms of coordinated methanol molecules, while [Cu(HL1)2] adopts a square planar geometry with the two (HL1) ligands in anti-conformation. Finally, the [M(HL2)2] complexes are octahedral with the two (HL2) ligands acting as κ-O,N,N-donors in planar conformation. Both the proligands and metal complexes were tested against the parasite Trypanosoma brucei and Balb3T3 cells. The Zn(II) complexes were found to be very powerful, more than the starting proligands, while maintaining a good safety level. In detail, H2L1 and its Zn(II) complex have high selective index (55 and >100, respectively) against T. brucei compared to the mammalian Balb/3T3 reference cells. These results encouraged the researchers to investigate the mechanism of action of these compounds that have no structural relations with the already known drugs used against T. brucei. Interestingly, the analysis of NTP and dNTP pools in T. brucei treated by H2L1 and its Zn(II) complex showed that the drugs had a strong impact on the CTP pools, making it likely that CTP synthetase is the targeted enzyme