María J. Gil

Surface-mediated improvement of enantioselectivity with clay-immobilized copper catalysts

The clay surface plays a role in the enantioselectivity of the cyclopropanation reaction, in the case of copper catalysts immobilized on laponite by electrostatic interactions. The effect is different depending on the type of chiral ligand, bis(oxazoline) or pyridineoxazoline. In the first case the clay promotes a reversal of the stereochemical course of the reaction. The pyridineoxazoline-copper complexes lead to very low enantioselectivity in homogeneous phase. However, the asymmetric induction increases when the complexes are immobilized on laponite, showing that it is possible to design good chiral ligands specific for the use in immobilized catalysts.

Efficient enhancement of copper-pyridineoxazoline catalysts through immobilization and process design

Copper-pyridineoxazoline (Cu-pyox) complexes are poor homogeneous catalysts for asymmetric cyclopropanation reactions. Pyox ligands have been immobilized by polymerization of monomers possessing a vinyl group directly attached to position 6 with styrene and divinylbenzene. The corresponding heterogeneous catalysts show a significant enhancement in enantioselectivity, up to 7-fold that of the analogous homogeneous Cu-pyox catalysts. This effect is due to a synergic effect between the proximity of the polymeric backbone and the presence of a bulky substituent in the chiral oxazoline ring around copper. The obtained values of enantioselectivity are similar to those found with supported C2-symmetric bis(oxazolines), but with only half the chiral information given the presence of only one oxazoline ring in pyox. Besides, the co-polymerization in the presence of the right porogen inside a column allows the preparation of monolithic mini-flow reactors. Continuous flow processes contribute to further improve the catalytic efficiency in both classical solvents (dichloromethane) and neoteric greener ones, such as supercritical CO2. The use of scCO2 as solvent yields the same selectivities obtained in batch processes in combination with higher productivity avoiding the use of VOC.

Are AM1 ligand‐protein binding enthalpies good enough for use in the rational design of new drugs?

We have examined the performance of semiempirical quantum mechanical methods in solving the problem of accurately predicting protein‐ligand binding energies and geometries. Firstly, AM1 and PM3 geometries and binding enthalpies between small molecules that simulate typical ligand‐protein interactions were compared with high level quantum mechanical techniques that include electronic correlation (e.g., MP2 or B3LYP). Species studied include alkanes, aromatic systems, molecules including groups with hypervalent sulfur or with donor or acceptor hydrogen bonding capability, as well as ammonium or carboxylate ions. B3LYP/6‐311+G(2d,p) binding energies correlated very well with the BSSE corrected MP2/6‐31G(d) values. AM1 binding enthalpies also showed good correlation with MP2 values, and their systematic deviation is acceptable when enthalpies are used for the comparison of interaction energies between ligands and a target. PM3 otherwise gave erratic energy differences in comparison to the B3LYP or MP2 approaches. As one would expect, the geometries of the binding complexes showed the known limitations of the semiempirical and DFT methods. AM1 calculations were subsequently applied to a test set consisting of “real” protein active site‐ligand complexes. Preliminary results indicate that AM1 could be a valuable tool for the design of new drugs using proteins as templates. This approach also has a reasonable computational cost. The ligand‐protein X‐ray structures were reasonably reproduced by AM1 calculations and the corresponding AM1 binding enthalpies are in agreement with the results from the “small molecules” test set.

Synthesis and cytotoxic activity of N-(2-pyridylsulfenyl)urea derivatives. A new class of potential antineoplastic agents

Starting from a 3D-model for the antineoplastic activity of diarylsulfonylureas several new features were proposed and tested. Both types of assayed compounds, the N-(2-pyridylsulfonyl)urea and N-(2-pyridylsulfenyl)urea derivatives, inhibited by 50% the growth of the CCRF-CEM cell line at a dosage near to 1 microM. The N -(2-pyrimidinyl) derivative of the sulfenylurea 6c showed a better profile against HT-29, K-562 and HTB-54 tumor cell lines than the corresponding sulfonylurea 6b. Structural modifications on aryl systems affected differently to the cytotoxic activity shown by the compounds against each cell line.

Benzo[b]thiophene-6-carboxamide 1,1-dioxides: Inhibitors of human cancer cell growth at nanomolar concentrations

Benzo[b]thiophenesulfonamide 1,1-dioxide derivatives (BTS) were described as candidate antineoplastic drugs. In the hope of finding new compounds with improved antitumour activity and reduced toxicity, we have designed and synthesized a small series of benzo[b]thiophene-6-carboxamide 1,1-dioxide derivatives (BTC) structurally related with the best reported BTS. Growth inhibition of HTB-54, CCRF-CEM and HeLa tumour cells lines at nanomolar concentrations was exhibited by some of the BTC. Hydrophobic substituents on the carboxamide group increased cytotoxicity but substitution by a hydroxy group diminished it, thus pointing to the electronic density on benzo[b]thiophene nucleus as a determinant factor. The process of cell death induced by BTC derivatives was further analyzed in CCRF-CEM cells, where these compounds induced apoptosis in a time and dose-dependent manner and cell cycle arrest at S phase. BTC derivatives also induced a significant increase in intracellular ROS levels in this cell line. Previous treatment of the cells with the antioxidant N-acetyl-cysteine abrogated the induction of apoptosis by BTC indicating that ROS generation is a previous event required to trigger the BTC induced apoptotic process.

Strawberry-like SiO2@Pd and Pt nanomaterials

Based on a synthesis strategy of silica nanoparticles (NPs) in non-alcoholic medium, a straightforward protocol leading to strawberry-like SiO2@M nanomaterials (M = Pt, Pd) has been developed. Pd and Pt NPs were immobilised onto surface modified silica NPs, by in situ decomposition of organometallic precursors, Pd2(dba)3 and Pt(dba)2 (dba = dibenzylideneacetone). The surface of silica was functionalised by aminopropyltriethoxysilane (APTES) or 2-(diphenylphosphino)ethyltriethoxysilane (PhPETES). The co-grafting of propyltriethoxysilane (PTES) and APTES was investigated to avoid the classical interfering cohydrolysis and polycondensation reactions which can lead to agglomeration phenomena between the silica NPs. It appeared that a APTES/PTES ratio of 1/3 insured a dense and homogeneous deposition of the metallic NPs onto silica. Depending on the ligand, the diameter of the metallic NPs varies from 3.6 to 6.0 nm for Pd and from 1.5 to 3.1 nm for Pt NPs. The metal loading is adjustable, at least up to 6.91 wt%, as exemplified with Pd. Preliminary catalytic tests of the SiO2@Pd nanomaterial are also presented.

Molecular modelling of the isothiazolo[5,4-b]pyridin-3(2H)-one derivatives

Abstract The performance of several semiempirical (MNDO, AM1, PM3, and SAM1) and ab initio (HF and MP2/6-31G ∗ ) methods for describing the structural and electronic features of a series of isothiazolopyridines, some of them bearing a hypervalent sulphur, is compared. Most of semiempirical methods calculate reasonable molecular structures, as compared with X-Ray structures, even in the case of S -oxides and S , S -dioxides. However, dipole moments are barely reproduced by these methods, even in the case of SAM1, which includes d orbitals. Hartree-Fock ab initio calculations do not lead to good dipole moment values in the case of S , S -dioxides. The agreement with experimental values is much better in the case of second order Moller-Plesset calculations, but this seems to be due to the systematic differences found between HF and MP2 values.

Immobilizing a single pybox ligand onto a library of solid supports

Chiral pyridinebis(oxazoline) (pybox) ligands can be efficiently immobilized onto silica through position 4 of the pyridine ring. The crucial intermediate in this strategy is 4-chloropybox, which is prepared in good yield from chelidamic acid. 4-Chloropybox reacts with p-hydroxybenzaldehyde and p-aminophenol to give two intermediates (pybox-CHO and pybox-NH2) that allow to introduce the formyl and amino groups able to link to spacers with triethoxysilylgroups. The modified ligands and their ruthenium complexes are immobilized by grafting onto pre-formed silicas or, alternatively, the support is created by sol-gel synthesis using the functionalizedchiral ligand as a silica monomer. In this way it is possible to create a library where the variation involves the support rather than the catalyst. The aim of this approach is to study the influence of different parameters, such as the textural properties of the support and the immobilization method, on the functionalization and catalytic performance. Some of the immobilized complexes are compared as heterogeneous catalysts in the cyclopropanation reaction of styrene with ethyl diazoacetate.

New 5-Substituted Derivatives of Ethyl 2,3-Dihydro-3-oxoisothiazolo[5,4-b]pyridine-2-acetate

New series of ethyl 5-substituted 2,3-dihydro-3-oxoisothiazolo[5,4-b] pyridine-2-acetate was prepared either a) directly by reaction of 5-substituted 2-chlorothio-3-pyridinecarbonyl chlorides with ethyl glycinate or b) by oxidation of the correspondent 2-mercapto-3-pyridine- carboxamides. New 5-substituted 1,2-dihydro-2-thioxo-3-pyridine- carboxylic acids as starting materials are described

Biomass Sources for Hydrogen Production

Biomass is a promising feedstock for the production of hydrogen. Within this chapter, current and future biomass resource potential are evaluated. The composition and properties of the most commonly used biomass feedstocks are also described. The required pretreatments of biomass prior to the conversion to hydrogen are discussed as a function of the biomass structure, composition and properties as well as the technology used for its transformation to hydrogen. A revision of the most common currently available methodologies for the production of hydrogen from biomass is also envisaged. Finally, life cycle assessment and costs will be considered for the currently developed technologies.