ABSTRACT
A longstanding challenge in catalysis by noble metals has been to understand the origin of enhancements of rates of hydrogen transfer that result from the bonding of oxygen near metal sites. We investigated structurally well-defined catalysts consisting of supported tetrairidium carbonyl clusters with single-atom (apical iridium) catalytic sites for ethylene hydrogenation. Reaction of the clusters with ethylene and H2 followed by O2 led to the onset of catalytic activity as a terminal CO ligand at each apical Ir atom was removed and bridging dioxygen ligands replaced CO ligands at neighboring (basal-plane) sites. The presence of the dioxygen ligands caused a 6-fold increase in the catalytic reaction rate, which is explained by the electron-withdrawing capability induced by the bridging dioxygen ligands, consistent with the inference that reductive elimination is rate-determining. Electronic-structure calculations demonstrate an additional role of the dioxygen ligands, changing the mechanism of hydrogen transfer from one involving equatorial hydride ligands to that involving bridging hydride ligands. This mechanism is made evident by an inverse kinetic isotope effect observed in ethylene hydrogenation reactions with H2 and, alternatively, with D2 on the cluster incorporating the dioxygen ligands and is a consequence of quasi-equilibrated hydrogen transfer in this catalyst. The same mechanism accounts for rate enhancements induced by the bridging dioxygen ligands for the catalytic reaction of H2 with D2 to give HD. We posit that the mechanism involving bridging hydride ligands facilitated by oxygen ligands remote from the catalytic site may have some generality in catalysis by oxide-supported noble metals.
ABSTRACT
Assessing the origin of asymmetric induction in heterogeneously catalyzed hydrogenation is a challenging task. In this work, hydrogenation of a chiral compound, (R)-1-hydroxy-1-phenyl-2-propanone [(R)-PAC], in toluene over cinchonidine modified and unmodified Pt/Al(2)O(3) was studied. To reveal the detailed reaction mechanism and the origin of stereoselectivity in the Pt-catalyzed hydrogenation of the CO double bond, the structures and energies of several adsorption modes of (R)-PAC as well as whole reaction paths for hydrogenation were investigated on Pt(111) by density functional theory (DFT). In agreement with experimental results, the theoretically obtained potential energy profiles for the studied hydrogenation mechanisms implied that (1R,2S)-1-phenyl-1,2-propanediol is formed in excess with respect to the other diastereomeric product diol, (1R,2R)-1-phenyl-1,2-propanediol. Generally, if the elementary hydrogen addition step was thermodynamically more favorable on one of the two diastereotopic faces, it was also kinetically preferred on the same face, and vice versa. Pairwise addition of hydrogen was the most energetically favorable mechanism. Adsorption and hydrogenation of other structurally similar chiral alpha-hydroxyketones, (R)-3-hydroxy-2-butanone and (R)-2-hydroxy-1-cyclohexanone, were also studied computationally on Pt(111). The results showed that cluster model DFT calculations can be used to assess (dia)stereoselectivity in metal-catalyzed hydrogenation of even such complex organic molecules as studied here.
Subject(s)
Chemistry, Organic/methods , Ketones/chemistry , Platinum/chemistry , Adsorption , Catalysis , Chalcones/chemistry , Hydrogen/chemistry , Hydrogenation , Kinetics , Molecular Conformation , Stereoisomerism , ThermodynamicsABSTRACT
Structures and conformational behavior of several cinchona alkaloid O-ethers in the solid state (X-ray), in solution (NMR and DFT), and in the gas phase (DFT) were investigated. In the crystal, O-phenylcinchonidine adopts the Open(3) conformation similar to cinchonidine, whereas the O-methyl ether derivatives of both cinchonidine and cinchonine are packed in the Closed(1) conformation. Dynamic equilibria in solutions of the alkaloids were revealed by combined experimental-theoretical spin simulation/iteration techniques for the first time. In the (1)H NMR spectra in CDCl3 and toluene-d8 at room temperature, Closed(1) conformation was observed for the O-silyl ethers as a separate set of signals. For O-methyl ether derivatives Closed(1) could be separated only at -30 degrees C in CDCl3 or toluene-d8 and for O-phenylcinchonidine at -70 degrees C in CDCl3/CD2Cl2. The ratio between the Closed(2) and Open(3) conformers was estimated by analyzing the vicinal coupling constant (3)J(H9,H8) at ambient and low temperatures. The observed conformational equilibria of O-(tert-butyldimethylsilyl)cinchonidine in CDCl 3 and toluene-d8 are in good agreement with the theoretically estimated equilibrium populations of the conformations according to Boltzmann statistics. The conformational equilibria of four cinchona alkaloid O-ether solutes in CDCl3 and toluene-d8 are discussed in the light of their relevance to the mechanism of 1-phenyl-1,2-propanedione (PPD) hydrogenation over cinchona alkaloid modified heterogeneous platinum catalysts. It was demonstrated that the conformation found to be abundant in the liquid phase has no direct correlation with the enantioselectivity of the PPD hydrogenation reaction.
Subject(s)
Algorithms , Cinchona Alkaloids/chemistry , Crystallography, X-Ray/methods , Ethers/chemistry , Magnetic Resonance Spectroscopy/methods , Catalysis , Chalcones/chemistry , Gases , Hydrogenation , Models, Chemical , Molecular Conformation , Platinum/chemistry , Solvents/chemistry , Stereoisomerism , TemperatureABSTRACT
Butyrylcholinesterase (BChE) inhibitors were identified from a collection containing cinchonine, cinchonidine and synthetic derivatives, and further characterized using cytotoxicity and molecular docking studies. The most active ones were: (10 triple bond)-10,11-dibromo-10,11-dihydrocinchonidine (11), a competitive inhibitor with Ki = 3.45 +/- 0.39 microM, and IC50 BChE = 9.83 +/- 0.30 microM/human (h)BChE = 34.47 +/- 4.63 and O-(trimethylsilyl)cinchonine (15), a mixed inhibitor with Kiuc = 1.73 +/- 0.46 microM and Kic = 0.85 +/- 0.26 microM, and IC50 BChE = 0.56 +/- 0.14 microM/hBChE = 0.24 +/- 0.04. In cytotoxicity experiments, > or = 80% of the cells remained viable when exposed to concentrations of up to 80 microM of both inhibitors in four different cell lines, including neurons. Due to the bulkier trimethylsilyl side group of 15, it covered the active site of hBChE better than 11 with an OH-group while not being able to fit into the active site gorge of hAChE, thus explaining the selectivity of 15 towards hBChE.
Subject(s)
Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Cinchona Alkaloids/chemistry , Cinchona Alkaloids/pharmacology , Butyrylcholinesterase , Cinchona/chemistry , Humans , Molecular Structure , Plant Bark/chemistry , Plant Stems/chemistry , Structure-Activity RelationshipABSTRACT
Bacterial biofilms are resistant to most of the commonly available antibacterial chemotherapies. Thus, an enormous need exists to meet the demands of effective anti-biofilm therapy. In this study, a small library of cinchona alkaloids, including the naturally occurring compounds cinchonidine and cinchonine, as well as various synthetic derivatives and analogues was screened for antibacterial and anti-biofilm activity against the Staphylococcus aureus biofilm producing strain ATCC 25923. Two methods were used to evaluate activity against biofilms, namely crystal violet staining to measure biomass and resazurin assay to measure biofilms viability. Cinchonidine was found to be inactive, whereas a synthetic derivative, 11-triphenylsilyl-10,11-dihydrocinchonidine (11-TPSCD), was effective against planktonic bacteria as well as in preventing biofilm formation at low micromolar concentrations. Higher concentrations were required to eradicate mature biofilms.
Subject(s)
Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Cinchona Alkaloids/pharmacology , Staphylococcus aureus/drug effects , Staphylococcus aureus/physiologyABSTRACT
Staining of Staphylococcus aureus biofilms with 20 microM resazurin during 20 min was shown to provide a good screening assay in 96-well micro titer plates. However, data quality was found to be dependent on the staining duration and biofilm concentration. Also, the inadequacy of using resazurin calibration curves with planktonic cells to estimate S. aureus biofilm concentrations was demonstrated.