The influence of conformation and aggregation on the hydrogen bond donor ability of fluorinated alcohol solvents [1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and 1-phenyl-2,2,2-trifluoroethanol (PhTFE)] was explored theoretically (DFT) and experimentally (NMR, kinetics, crystal structure analyses). The detailed DFT analysis revealed a pronounced dependence of the H-bond donor ability on the conformation along the CO-bond of the monomeric alcohols. The donor orbital energy (sigma*(OH)) decreases and the molecular dipole moment (mu) increases drastically from the antiperiplanar (ap) to the synperiplanar (sp) H(C)COH conformation. The kinetics of olefin epoxidation with H(2)O(2) in HFIP indicate higher order solvent aggregates (2-3 monomers) to be responsible for the activation of the oxidant. Single-crystal X-ray analyses of HFIP and PhTFE confirmed the existence of H-bonded aggregates (infinite helices, ribbons, and cyclic oligomers) and the predominance of sc to sp conformations of the fluoroalcohol monomers. These aggregate structures served as the basis for a DFT analysis of the H-bond donor ability at the terminal hydroxyl group of HFIP mono- to pentamers. Both the LUMO energy and the natural charge of the terminal hydroxyl proton indicated a substantial cooperative influence of dimerization and trimerization on the H-bond donor ability. We therefore conclude that dimers and trimers, with the individual monomers in their sc to sp conformation, play a crucial role for the solvolytic and catalytic effects exerted by HFIP, rather than monomers.
Titanium Silicalite-1 (TS-1) shows an outstanding ability to catalytically epoxidize olefins with hydrogen peroxide (H2O2), leaving only water as byproduct. 1,2 Despite the industrial use of the TS-1/H2O2 system for the production of more than one million tons of propylene oxide per year, 3 the active site structure remains elusive, although it has been studied for almost 40 years by spectroscopic and computational methods. 4-10 TS-1 is a zeotype of MFI structure in which a small fraction of Si-atoms (1-2 %) are substituted by Ti, and its catalytic properties are generally attributed to isolated Ti(IV) sites. 1 Herein, we analyze a series of highly active and selective TS-1 propylene epoxidation catalysts. By UV-Vis and Raman spectroscopy, as well as electron microscopy, we show that Ti is well-dispersed in all samples, with formation of small TiOx clusters at high Ti-loadings. Most notably, irrespective of Ti-content, all samples show a characteristic solid-state 17 O NMR signature when contacted with H2 17 O2, indicating the formation of bridging peroxo species on dinuclear Tisites. Using DFT (density functional theory) calculations, we propose a mechanism of propylene epoxidation on a dinuclear site, in which the cooperativity between two titanium atoms enables a low-energy reaction pathway where the key oxygen-transfer transition state bears strong resemblance to that of olefin epoxidation by peracids.The active species in TS-1 are commonly proposed to be isolated Ti(IV) sites bearing peroxo 11 or hydroperoxo moieties, 12 although the involvement of terminal Ti-oxo and activated H2O2 on Ti(IV) has also been discussed (Fig. 1a,b). 7 In contrast, the only homogeneous Ti-based epoxidation catalysts able to efficiently utilize H2O2 as primary oxidant are dinuclear, such as the Berkessel-Katsuki epoxidation catalyst 1 (Fig. 1c). [14][15][16][17][18][19] While the structural characterization of molecular systems is well-established and has enabled the isolation of peroxo compounds, obtaining information on the structure of Ti-sites in TS-1 with molecular-level precision has proven more challenging.Recent work by some of us has shown that solid-state 17 O NMR spectroscopy is a powerful tool for understanding and assessing the reactivity of peroxo species. 20 Oxygen-17 is an NMRactive quadrupolar nucleus whose spectroscopic properties can be readily measured by solidstate NMR and computed by DFT. The NMR signature (chemical shift and quadrupolar coupling) is highly sensitive to the symmetry and electronic structure around the oxygen atoms. We thus reasoned that 17 O NMR spectroscopy would be a valuable tool to harness the signature of the active sites in TS-1 and thereby probe their structure. In this study, we investigate five TS-1 samples prepared in the BASF laboratories (Table 1). 21,22 Two of these samples have a Ti-content of 1.9 wt%, one of which was prepared on hundred-kg scale (sample 1), the other three samples have Ti-loadings of 1.5 wt%, 1.0 wt%, and 0.5 wt%. The five samples have surface areas between 4...
The hydrogenation of unsaturated organic substrates such as olefins and ketones is usually effected by homogeneous or heterogeneous transition-metal catalysts. On the other hand, a single case of a transition-metal-free and purely base-catalyzed hydrogenation of ketones was reported by Walling and Bollyky some 40 years ago. Unfortunately, the harsh reaction conditions (ca. 200 degrees C, >100 bar H(2), potassium tert-butoxide as base) limit the substrate spectrum of this reaction to robust, nonenolizable ketones such as benzophenone. We herein present a mechanistic study of this process as a basis for future rational improvement. The base-catalyzed hydrogenation of ketones was found to be irreversible, and it shows first-order kinetics with respect to the substrate ketone, hydrogen, and catalytic base. The rate of the reaction depends on the type of alkali ion present (Cs > Rb - K >> Na >> Li). Using D(2) instead of H(2) revealed a rapid base-catalyzed isotope exchange/equilibration between the gas phase and the solvent as a concomitant reaction. The degree of deuteration of the product alcohols did not indicate a significant kinetic isotope effect. It is proposed that both ketone reduction and isotope exchange proceed via similar six-membered cyclic transition states involving the H(2)(D(2))-molecule, the alkoxide base, and the ketone (solvent alcohol in the case of isotope exchange). Mechanistic analogies are pointed out which apparently exist between the base-catalyzed hydrogenation of ketones studied here and the Ru-catalyzed asymmetric ketone hydrogenation developed by Noyori. In both cases, heterolysis of the hydrogen molecule appears to be assisted by a Brønsted-base (i.e., alkoxide), the latter being bound to the substrate ketone or the catalyst ligand, respectively, by a bridging Lewis-acidic alkali ion.
In 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as solvent, the epoxidation of olefins by hydrogen peroxide is accelerated up to ca. 100 000-fold (relative to that in 1,4-dioxane as solvent). The mechanistic basis of this effect was investigated kinetically and theoretically. The kinetics of the epoxidation of Z-cyclooctene provided evidence that higher-order solvent aggregates (rate order in HFIP ca. 3) are responsible for the rate acceleration. Activation parameters (DeltaS++ = -39 cal/mol.K) indicated a highly ordered transition state in the rate-determining step. In line with these findings, DFT simulations revealed a pronounced decrease of the activation barrier for oxygen transfer from H(2)O(2) to ethene with increasing number of (specifically) coordinated HFIP molecules. The oxygen transfer was unambiguously identified as a polar concerted process. Simulations (combined DFT and MP2) of the epoxidation of Z-butene were in excellent agreement with the experimental data obtained in the epoxidation of Z-cyclooctene (activation enthalpy, entropy, and kinetic rate order in HFIP of 3), supporting the validity of our mechanistic model.
High amounts of acrylamide in some foods result in an estimated daily mean intake of 50 Mg for a western style diet. Animal studies have shown the carcinogenicity of acrylamide upon oral exposure. However, only sparse human toxicokinetic data is available for acrylamide, which is needed for the extrapolation of human cancer risk from animal data. We evaluated the toxicokinetics of acrylamide in six young healthy volunteers after the consumption of a meal containing 0.94 mg of acrylamide. Urine was collected up to 72 hours thereafter. Unchanged acrylamide, its mercapturic acid metabolite N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA), its epoxy derivative glycidamide, and the respective metabolite of glycidamide, N-acetyl-S-(2-hydroxy-2-carbamoylethyl)cysteine (GAMA), were quantified in the urine by liquid chromatography-mass spectrometry. Toxicokinetic variables were obtained by noncompartmental methods. Overall, 60.3 F 11.2% of the dose was recovered in the urine. Although no glycidamide was found, unchanged acrylamide, AAMA, and GAMA accounted for urinary excretion of (mean F SD) 4.4 F 1.5%, 50.0 F 9.4%, and 5.9 F 1.2% of the dose, respectively. Apparent terminal elimination half-lives for the substances were 2.4 F 0.4, 17.4 F 3.9, and 25.1 F 6.4 hours. The ratio of GAMA/AAMA amounts excreted was 0.12 F 0.02. In conclusion, most of the acrylamide ingested with food is absorbed in humans. Conjugation with glutathione exceeds the formation of the reactive metabolite glycidamide. The data suggests an at least 2-fold and 4-fold lower relative internal exposure for glycidamide from dietary acrylamide in humans compared with rats or mice, respectively. This should be considered for quantitative cancer risk assessment. (Cancer Epidemiol Biomarkers Prev 2006;15(2):266 -71)
54 years later: Saturated imidazolidin‐2‐ylidenes react with aldehydes to smoothly produce the elusive 2,2‐diamino enols A (“Breslow intermediates”, first postulated in 1958) of carbene‐catalyzed umpolung reactions. The 2,2‐diamino enols A react with additional aldehyde in a cross‐benzoin reaction. The methylated Breslow intermediates B are accessible by deprotonation of methoxymethyl azolium salts.
Measure what is measurable, and make measurable what is not so! This timeless quotation by Galileo forms the basis of all quantitative understanding, including asymmetric organocatalysis. We report pKa values for 15 chiral Brønsted acid catalysts in DMSO solutions (see scheme): the strongest acids were bis‐sulfonyl/sulfuryl imides (pKa=1.7–1.9) followed by phosphoric acids/amides (pKa=2.4–4.2). A new class of chiral Brønsted acids, tetrakis‐perfluoroalkyl analogues of TADDOLs (TEFDDOLs) have pKas from 2.4 to 5.7.
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