Determination of enantiomerization barriers by dynamic and stopped‐flow chromatographic methods

Trapp, Oliver; Schoetz, Gabriele; Schurig, Volker

doi:10.1002/chir.1052

Cited by 210 publications

(152 citation statements)

References 94 publications

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“…[6] A unique technique for studying configurational changes in chiral compounds is dynamic chromatography [7] combining molecular interconversion and analysis under precisely controlled conditions. Recently, we reported [8] a unified equation to directly access reaction rate constants of first-order reactions of such experiments.…”

Section: Dedicated To Süd-chemie On the Occasion Of Its 150th Annivermentioning

confidence: 99%

High‐Throughput Screening of Catalysts by Combining Reaction and Analysis

et al. 2007

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Dedicated to Süd-Chemie on the occasion of its 150th anniversaryDiscovering new catalysts is crucial to the development of sustainable chemical processes for industrial applications as well as for broadening the spectrum of synthetic methodologies and techniques in chemistry. The prerequisite for the directed design of catalysts is understanding how the kinetics, in other words, the activation barrier, in the mechanism of catalysis is controlled by the structural parameters.[1] To identify rate-determining elementary steps and to develop models, comprehensive experimental kinetic data of a broad variety of substrates are necessary. Microfluidic devices integrating chemical synthesis and analysis on the same chip [2][3][4][5] are one promising approach for parallelized highthroughput (ht) kinetic measurements of catalysts with minute material consumption.[6] A unique technique for studying configurational changes in chiral compounds is dynamic chromatography [7] combining molecular interconversion and analysis under precisely controlled conditions. Recently, we reported [8] a unified equation to directly access reaction rate constants of first-order reactions of such experiments. However, commonly used (micro)reactors, in which the reaction, separation, and quantification of conversion are performed consecutively, are limited to the study of single reactions, because competing reactions lead to undefinable reaction kinetics. Here we show for the hydrogenation over highly active Pd nanoparticles and the ring-closing metathesis over the Grubbs second generation catalyst that the synchronous combination of catalysis and separation makes it possible to efficiently perform ht reaction rate measurements (147 reactions per hour) of substrate libraries. The catalytic systems for these multiphase reactions (gas-liquid-solid) were prepared by embedding the catalysts in polysiloxanes, which serve as both solvent and selective stationary separation phase. Furthermore this system can be used for cascade reactions or for preparative synthesis to produce the target compounds.Typically, multiphase catalytic systems, which play a predominant role in industrial processes, are difficult to investigate because the interaction of the substrate with the catalyst is controlled by the mass transfer between the different phases, and therefore the apparent reaction rate is composed of the inherent reaction rate and diffusion rates. To reduce this effect, the interfacial area must be increased. Microstructured reaction systems intrinsically have a high specific interfacial area per volume, only dependent on the radius of the reaction channels; that is, for capillaries with inner diameters between 250 and 100 mm the specific interfacial area per volume ranges from 16 000 to 40 000 m 2 m À3 . Microfluidic systems are currently revolutionizing chemical synthesis, [9][10][11][12][13] because physical processes can be more easily controlled, low operation volumes minimize reagent consumption, and detection is integrated.[14] However, there are s...

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Section: Dedicated To Süd-chemie On the Occasion Of Its 150th Annivermentioning

confidence: 99%

High‐Throughput Screening of Catalysts by Combining Reaction and Analysis

et al. 2007

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“…The process of enantio-merization has been previously reported in GC, HPLC, and CE for the chiral separation of benzodiazepinones. [68][69][70] This phenomenon often results in plateau formation and ultimately peak coalescence. The three chiral benzodiazepinones studied have similar molecular structure, differing only by the presence of chloro group on the phenyl ring and methyl group at the amide nitrogen in the benzodiazepinone skeleton ( Figure 4).…”

Section: Enantioseparation Of (±)-Benzodiazepinesmentioning

confidence: 99%

Polymeric Sulfated Amino Acid Surfactants: A Class of Versatile Chiral Selectors for Micellar Electrokinetic Chromatography (MEKC) and MEKC-MS

et al. 2006

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In this work, three amino acids derived (L-leucinol, L-isoleucinol and L-valinol) sulfated chiral surfactants are synthesized and polymerized. These chiral sulfated surfactants are thoroughly characterized to determine critical micelle concentration, aggregation number, polarity, optical rotation and partial specific volume. For the first time the morphological behavior of polymeric sulfated surfactants is revealed using cryogenic high-resolution electron microscopy (cryo-HRSEM). The polysodium N-undecenoyl-L-leucine sulfate (poly-L-SUCLS) shows distinct tubular structure, while polysodium N-undecenoyl-L-valine sulfate (poly-L-SUCVS) also shows tubular morphology but without any distinct order of the tubes. On the other hand, polysodium N-undecenoyl-Lisoleucine sulfate (poly-L-SUCILS) displays random distribution of coiled/curved filaments with heavy association of tightly and loosely bound water. All three polymeric sulfated surfactants are compared for enantio-separation of broad range of structurally diverse racemic compounds at very acidic, neutral and basic pH conditions in micellar electrokinetic chromatography (MEKC). A small combinatorial library of 10 structurally related phenylethylamines (PEAs) is investigated for chiral separation under acidic and moderately acidic to neutral pH conditions using an experimental design. In contrast to neutral pH conditions, at acidic pH, significantly enhanced chiral resolution is obtained for class I and class II PEAs due to the compact structure of polymeric sulfated surfactants. It is observed that the presence of hydroxy group on the benzene ring of PEAs resulted in deterioration of enantioseparation. A sensitive MEKC-mass spectrometry (MS) method is developed for one of the PEA (e.g., (±)-pseudoephedrine) in human urine. Very low limit of detection (LOD) is obtained at pH 2.0 (LOD 325 ng/mL), which is ca 16 times better compared to pH 8.0 (LOD 5.2 µg/mL). Other broad range of chiral analytes (β-blockers, phenoxypropionic acid, benzoin derivatives, PTHamino acids, and benzodiazepinones) studied also provided improved chiral separation at low pH compared to high pH conditions. Among the three polymeric sulfated surfactants, poly-L-SUCILS with two chiral centers on the polymer head group provided overall higher enantioresolution for the investigated acidic, basic and neutral compounds. This work clearly demonstrates for the first time the superiority of chiral separation and sensitive MS detection at low pH over conventional high pH chiral separation and detection employing anionic chiral polymeric surfactants in MEKC and MEKC-MS. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptOver the last 20 years, the number of materials and products developed as pure enantiomers (eutomer) has continued to increase. With evidence of problems related to stereoselectivity in drug action, enantioselective analysis by separation are of particular importance for production, therapeutic monitoring or pharmacokinetic studies, and/or to validate the opt...

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“…4c) affords a straight line, which suggests a first order kinetics of interconversion for the atropisomers of 1. [8][9][10] The rate constant for atropisomer interconversion can be readily derived using the slope of the linear plot (1.23 3 10 25 sec 21 ), which is more conveniently expressed as a half life (7.8 h).…”

Section: Resultsmentioning

confidence: 99%

Factors influencing the interconversion of a new class of dibenzodiazepine sulfonamide atropisomers

et al. 2009

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A novel family of atropisomers based on a conformationally constrained seven membered ring system is investigated using a combination of preparative chiral chromatography, circular dichroism, and other analytical techniques. The influence of structure on the rate of atropisomer interconversion was explored with a series of analogs showing a range of interconversion rates ranging from very fast (undetectable on the HPLC timescale) to very slow (half life of many days).

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Determination of enantiomerization barriers by dynamic and stopped‐flow chromatographic methods

Cited by 210 publications

References 94 publications

High‐Throughput Screening of Catalysts by Combining Reaction and Analysis

High‐Throughput Screening of Catalysts by Combining Reaction and Analysis

Polymeric Sulfated Amino Acid Surfactants: A Class of Versatile Chiral Selectors for Micellar Electrokinetic Chromatography (MEKC) and MEKC-MS

Factors influencing the interconversion of a new class of dibenzodiazepine sulfonamide atropisomers

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