Access to modified geiparvarins using Pd(0)-mediated C-C bond forming reactions

Geiparvarin is a natural product which contains both a 3(2H)-furanone and a coumarin moiety in its structure. The aim of this project was to investigate the use of Pd(0)-mediated C–C bondforming reactions to produce structurally modified geiparvarins. Chapter 1 consists of a review of the relevant literature, including that pertaining to the syntheses of selected naturally occurring 3(2H)-furanones. The known syntheses of geiparvarin and closely related analogues are examined, along with the documented biological activity of these compounds. The synthetic routes which allow access to 4-substituted-3(2H)-furanones are also described. Chapter 2 describes in detail the synthesis of a variety of novel structurally modified geiparvarins by two complementary routes, both approaches utilising Pd(0)-mediated crosscoupling reactions, and discusses the characterisation of these compounds. The preparation of 5-ethyl-3(2H)-furanones is described, as is their incorporation into geiparvarin and the corresponding 5″-alkylgeiparvarin analogues via formation and dehydration of intermediate alcohols. Halogenation of 5-ethyl-3(2H)-furanones and the corresponding geiparvarin derivatives is discussed, along with further reactions of the resulting halides. Preparation of 3″-arylgeiparvarins involving both Suzuki–Miyura and Stille reactions, using the appropriate intermediate iodides and bromides, is described. The application of Stille and Heck conditions to give 3″-ethenylgeiparvarin analogues and Sonogashira conditions to produce 3″-ethynylgeiparvarin analogues, using the relevant intermediate iodides, is also extensively outlined. Chapter 3 contains all of the experimental data and details of the synthetic methods employed for the compounds prepared during the course of this research. All novel compounds prepared were fully characterised using NMR spectroscopy, IR spectroscopy, mass spectrometry and elemental analysis; the details of which are included.

A first principles study of methanol decomposition on Pd(111): Mechanisms for O-H bond scission and C-O bond scission

There is some dispute as to whether methanol decomposition occurs by O-H bond scission or C-O bond scission. By carrying out density functional theory calculations, we investigate both scenario of the reaction pathways of methanol decomposition on a Pd(111) surface. It is shown that the O-H bond scission pathway is much more energetically favorable than the C-O bond scission pathway. The high reaction barrier in the latter case is found to be due to the poor bonding abilities of CH3 and OH with the surface at the reaction sites. (C) 2001 American Institute of Physics.

MErCuRIC1: A Phase I study of MEK1/2 inhibitor PD-0325901 with cMET inhibitor crizotinib in RASMT and RASWT (with aberrant c-MET) metastatic colorectal cancer (mCRC) patients.

Background: RAS is mutated (RASMT) in ~55% of mCRC, and phase III studies have shown that patients harbouring RAS mutations do not benefit from anti-EGFR MoAbs. In addition, ~50% of RAS Wild Type (RASWT) will not benefit from the addition of an EGFR MoAb to standard chemotherapy. Hence, novel treatment strategies are urgently needed for RASMT and > 50% of RASWT mCRC patients. c-MET is overexpressed in ~50-60%, amplified in ~2-3% and mutated in ~3-5% of mCRC. Recent preclinical studies have shown that c-MET is an important mediator of resistance to MEK inhibitors (i) in RASMT mCRC, and that combined MEKi/METi resulted in synergistic reduction in tumour growth in RASMT xenograft models (1). A number of recent studies have highlighted the role of c-MET in mediating primary/secondary resistance to anti-EGFR MoAbs in mCRC, suggesting that patient with RASWT tumours with aberrant c-MET (RASWT/c-MET+) may benefit from anti-c-MET targeted therapies (2). These preclinical data supported the further clinical evaluation of combined MEKi/METi treatment in RASMT and RASWT CRC patients with aberrant c-MET signalling (overexpression, amplification or mutation; RASWT/c-MET+). Methods: MErCuRIC1 is a phase I combination study of METi crizotinib with MEKi PD-0325901. The dose escalation phase, utilizing a rolling six design, recruits 12-24 patients with advanced solid tumours and aims to assess safety/toxicity of combination, recommended phase II (RPII) dose, pharmacokinetics (PK) and pharmacodynamics (PD) (pERK1/2 in PBMC and tumour; soluble c-MET). In the dose expansion phase an additional 30-42 RASMT and RASWT/c-MET mCRC patients with biopsiable disease will be treated at the RPII dose to further evaluate safety, PK, PD and treatment response. In the dose expansion phase additional biopsy and blood samples will be obtained to define mechanisms of response/resistance to crizotinib/PD-0325901 therapy. Enrolment into the dose escalation phase began in December 2014 with cohort 1 still ongoing. EudraCT registry number: 2014-000463-40. (1) Van Schaeybroeck S et al. Cell Reports 2014;7(6):1940-55; (2) Bardelli A et al. Cancer Discov 2013;3(6):658-73. Clinical trial information: 2014-000463-40.

Potential oscillations in a proton exchange membrane fuel cell with a Pd-Pt/C anode

We report in this paper the occurrence of potential oscillations in a proton exchange membrane fuel cell (PEMFC) with a Pd-Pt/C anode, fed with H(2)/100 ppm CO, and operated at 30 degrees C. We demonstrate that the use of Pd-Pt/C anode enables the emergence of dynamic instabilities in a PEMFC. Oscillations are characterized by the presence of very high oscillation amplitude, ca. 0.8 V. which is almost twice that observed in a PEMFC with a Pt-Ru/C anode under similar conditions. The effects of the H(2)/CO flow rate and cell current density on the oscillatory dynamics were investigated and the mechanism rationalized in terms of the CO oxidation and adsorption processes. We also discuss the fundamental aspects concerning the operation of a PEMFC under oscillatory regime in terms of the benefit resulting from the higher average power output. (c) 2010 Elsevier B.V. All rights reserved.

1,3-dipolar cycloaddition of CS2 to the coordinated azide in the cyclopalladated [Pd(bzan)(mu-N-3)](2). Crystal and molecular structure of di(mu-N,S-1,2,3,4-thiatriazole-5-thiolate)bis[(benzylideneaniline-C-2,N)palladium(II)]

The compound [Pd(bzan)(mu -N-3)](2) 1, bzan = benzylideneaniline, was prepared from [Pd(bzan) (mu -OOCCH3)](2) by an anion exchange reaction. The 1,3-dipolar cycloaddition of carbon disulfide to the bridged coordinated azide in the cyclometallated compound I was investigated. The species resulting from this reaction, di(mu -N,S-1,2,3,4-thiatriazol-5-thiolate)bis[(benzylideneaniline)palladium(II)] 2, was characterized by IR spectroscopy and X-ray diffraction. The compound 2 is a dimer containing two [Pd(benzylideneaniline)] moieties connected by two vicinal bridging N,S-1,2,3,4-thiatriazole-5-thiolate anions in a square-planar coordination geometry for the palladium atoms.

Cycloaddition reaction of the azido-bridged cyclometallated complex [Pd(dmba)N-3](2) with CS2. Crystal and molecular structure of DI(mu, N,S-1,2,3,4-thiatriazole-5-thiolate) bis[(N,N-dimethylbenzyl-amine-C-2,N)palladium(II)]

The 1,3-dipolar cycloaddition of carbon disulfide to the coordinated azide in the cyclometallated compound [Pd(dmba)(N-3)](2) (1), dmba = N,N-dimethylbenzylamine, was investigated. The compound obtained di(mu, N,S-1,2,3,4-thiatriazole-5-thiolate)-bis[(N,N-dimethylbenzylamine-C-2,N)palladium(II)] (2), was characterized by IR spectroscopy and X-ray diffraction. Complex (2) is dimeric with the two [Pd(N,N-dimethylbenzylamine)] moieties being connected by the two vicinal bridging N,S-1,2,3,4-thiatriazole-5-thiolate anions in a square-planar coordination for the palladium atoms.

Mono- and dinuclear palladium(II) compounds containing nitrogen ligands. Crystal and molecular structure of [Pd(N,C-dmba)(NCO)(2,3-lut)] and [Pd(H2CCOMe)Cl(2,2 '-bipy)]

The cyanate-bridged cyclopalladated compound [Pd(N,C-dmba)(mu-NCO)](2) (1) (dmba = PhCH2NMe2) reacts in CH2Cl2 with 2,3-lutidine (2,3- lut), 3,4-lutidine (3,4-lut), 2,2'-bipyridine (2,2'-bipy) and 4,4'-bipyridine (4,4'-bipy), to give [Pd(N, C-dmba)(NCO)(2,3-lut)] (2), [Pd(N,C-dmba)(NCO)(3,4-lut)] (3), [{Pd(N,C-dmba)(NCO)}(2)(mu-2,2'-bipy)] .CH2Cl2 (4) and [{Pd(N,C-dmba)(NCO)}(2)(mu-4,4'-bipy)] . CH2Cl2 (5), respectively. The compounds were characterized by elemental analysis, i.r. and n. m. r. spectroscopy and also by t.g.a. The i.r. spectra of (2 - 5) display typical bands of monodentate N-bonded cyanate groups, whereas the n. m. r. data of (4) are consistent with the presence of a bridging 2,2'-bipyridine ligand. Complex (4) decomposes slowly in acetone. One of the products formed, [Pd(H2CCOMe) Cl(2,2'-bipy)] (6), was characterized by X-ray diffraction. As inferred from the t.g.a., the thermal stability decreases in the order: [{Pd(N,C-dmba)(NCO)}(2) (mu-4,4'-bipy)]. CH2Cl2 (5) > [Pd(N,C-dmba)(2,3-lut)( NCO)] (2) = [Pd(N, C-dmba)(3,4-lut)(NCO)] (3) > [{Pd(N,C-dmba)(NCO)}(2)(mu- 2,2'-bipy)] .CH2Cl2 (4). According to thermal analysis and X-ray diffraction patterns compounds (2 - 3) decompose into metallic palladium Pd(0), whereas (4 - 5) decompose with the formation of PdO. The X-ray crystal and molecular structure of [Pd(N, C-dmba)( NCO)(2,3-lut)] (2) was determined. The lutidine unit is perpendicular to the coordination plane.

Crystal structure of di-mu(N,S)-thiocyanato-bis[(N-benzylideneaniline-C-2,N)palladium(II)], [Pd(C6H4CH=NC6H5)(mu-SCN)](2)

C28H20N4Pd2S2, monoclinic, P12(1)/c1 (No. 14), a = 11.325(1) Angstrom, b = 13.530(1) Angstrom, c = 17.925(1) Angstrom, beta = 106.23(1)degrees, V = 2637.1 Angstrom(3), Z = 4, R-gt(F) = 0.052, wR(ref)(F-2) = 0.129, T = 293 K.

Crystal structure of di-μ(N,S)-thiocyanato-bis[(N-benzylideneaniline-C 2,N)palladium(II)], [Pd(C6H4CH=NC 6H5)(μ-SCN)]2

C28H20N4Pd2S2, monoclinic, P121/c1 (No. 14), a = 11.325(1) Å, b = 13.530(1) Å, c = 17.925(1) Å, β = 106.23(1)°, V = 2637.1 Å 3, Z = 4, Rgt(F) = 0.052, wRref(F2) = 0.129, T = 293 K. © by Oldenbourg Wissenschaftsverlag.

Desenvolvimento de catalisadores sem platina: estudos comparativos da oxidação de metanol em 'PD''RU'/'C' e 'PT''RU'/'C' em meio alcalino

Pós-graduação em Química - IQ

Hydrogen spillover mechanism on a pd-doped mg surface as revealed by ab initio density functional calculation

The hydrogenation kinetics of Mg is slow, impeding its application for mobile hydrogen storage. We demonstrate by ab initio density functional theory (DFT) calculations that the reaction path can be greatly modified by adding transition metal catalysts. Contrasting with Ti doping, a Pd dopant will result in a very small activation barrier for both dissociation of molecular hydrogen and diffusion of atomic H on the Mg surface. This new computational finding supports for the first time by ab initio simulationthe proposed hydrogen spillover mechanism for rationalizing experimentally observed fast hydrogenation kinetics for Pd-capped Mg materials.

Au-Pd alloy nanoparticle catalyzed selective oxidation of benzyl alcohol and tandem synthesis of imines at ambient conditions

Alloy nanoparticles (NPs) of gold and palladium on ZrO2 support (Au–Pd@ZrO2) were found to be highly active in oxidation of benzyl alcohols and can be used for the tandem synthesis of imines from benzyl alcohols and amines via a one-pot, two-step process at mild reaction conditions. The first step of the process is oxidation of benzyl alcohol to benzaldehyde, excellent yields were achieved after 7 h reaction at 40 °C without addition of any base. In the second step, aniline was introduced into the reaction system to produced N-benzylideneaniline. The benzaldehyde obtained in the first step was completely consumed within 1 h. A range of benzyl alcohols and amines were investigated for the general applicability of the Au–Pd alloy catalysts. It is found that the performance of the catalysts depends on the Au–Pd metal contents and composition. The optimal catalyst is 3.0 wt% Au–Pd@ZrO2 with a Au:Pd molar ratio 1:1. The alloy NP catalyst exhibited superior catalytic properties to pure AuNP or PdNP because the surface of alloy NPs has higher charge heterogeneity than that of pure metal NPs according to simulation of density function theory (DFT)