SummaryA new approach for the investigation of a higher-order reaction by on-column reaction gas chromatography is presented. The reaction and the analytical separation are combined in a single experiment to investigate the Diels–Alder reaction of benzenediazonium-2-carboxylate as a benzyne precursor with various anthracene derivatives, i.e. anthracene, 9-bromoanthracene, 9-anthracenecarboxaldehyde and 9-anthracenemethanol. To overcome limitations of short reaction contact times at elevated temperatures a novel experimental setup was developed involving a cooling trap to achieve focusing and mixing of the reactants at a defined spot in a fused-silica capillary. This trap functions as a reactor within the separation column in the oven of a gas chromatograph. The reactants are sequentially injected to avoid undefined mixing in the injection port. An experimental protocol was developed with optimized injection intervals and cooling times to achieve sufficient conversions at short reaction times. Reaction products were rapidly identified by mass spectrometric detection. This new approach represents a practical procedure to investigate higher-order reactions at an analytical level and it simultaneously provides valuable information for the optimization of the reaction conditions.
The Cu-free 1,3-dipolar cycloaddition of cyclooctynes and azides is an up-and-coming method in bioorganic chemistry and other disciplines. However, broad application is still hampered by major drawbacks such as poor solubility of the reactants in aqueous media and low reaction rates. It is thus of high demand to devise a fast and user-friendly strategy for the optimization of reaction conditions and reagent design. We describe a capillary electrophoresis (CE) study of reaction kinetics in strain-promoted azide-alkyne cycloadditions (SPAAC) using substrates with acidic or basic functionalities. This study reveals that the pH value has a significant effect on reaction rates as a result of changes in the reactants' charge state via protonation or deprotonation, and the concomitant changes of electronic properties. This novel experimental setup also enables the study of even more challenging conditions such as reactions in micelles and we did indeed observe much faster SPAAC reactions in the presence of surfactants. Careful combination of the above-mentioned parameters resulted in the identification of conditions enabling remarkable rate enhancement by a factor of 80. This electrophoretic method may thus serve as a versatile, fast and reliable tool for screening purposes in all research areas applying SPAAC reactions.
As creeningp latform, which offers ah ighthroughput approach as well as an easy investigation of kinetic isotope effects,a pplicable to aw ide range of reactions is presented. To illustrate the high potential of this approach, the asymmetric transfer hydrogenation of methyl benzoylformate with copper(II) bis(oxazoline) and Hantzsch ester was examined. Accordingly,t he enantioselectivitieso ft he reaction performed on-column in am icrocapillary were comparable to standard reaction conditions, however, we were able achieve catalysis and analysis in as ingle step in less than 30 min. Thet hroughput can be increasedb ys imultaneous investigation of different substratesw ithout increasing the overall analysis time.U se of di-deuterated Hantzsch ester allowed us to investigate the kinetic isotope effect of the transfer hydrogenation reactiono nly requiring am inute amount of the deuterated transfer hydrogenation reagent. Hence we were able to get further insights into the mechanism of the asymmetric transfer hydrogenation using Hantzsch ester as hydrogen source.T he here presented technique is broadly applicable to studyi sotope effects on av ery small scale,w hich is ar apid and an inexpensivea lternative comparedtoc onventional experiments.Keywords: asymmetric transfer hydrogenation;c opper(II) bis(oxazoline);H antzsch ester;h igh-throughput;k inetic isotope effect;o n-column reaction gas chromatography
Characterising chemical reactions by kinetic analysis is of fundamental importance to experimentally obtain insights into reaction mechanisms. Based on such investigations reactions can be optimised and improved catalysts designed. Enhanced reaction conditions may drastically increase the performance of the reaction in terms of yield and (enantio-) selectivity. Understanding reaction kinetics in more complex systems involving adaptive chemical and dynamic systems on a molecular level as shown here is even more challenging. Here we review recent developments in monitoring reactions including the dynamic interconversion of stereoisomers by integrating (catalysed) reactions and chemical analysis in on-column reaction chromatographic devices. These recent developments allow rapid screening of reactions in great detail and are a central tool in determining reaction pathways and to understand how to control the stereodynamics of chiral molecules.
The catalytic activity of novel bidentate N,N-chelated palladium complexes derived from electron excessive, backbone fused 3,3′-bipyrazoles in the selective isomerization of terminal arylpropenoids and 1-alkenes is described. The catalysts are easily modified by appropriate wing tip substitution, while maintaining the same bulky, rigid unreactive aliphatic backbone. Eleven novel palladium complexes with different electronic and steric properties were investigated. Their performance in the palladium(II)-catalyzed isomerization of a series of substituted allylbenzenes was evaluated in terms of electronic as well as steric effects. Besides the clear finding of a general trend towards higher catalyst activity with more electron-donating properties of the coordinated N,N-bidentate ligands, we found that the catalytic process strongly depends on the choice of solvents and additives. Extensive solvent screening revealed that reactions run best in a 2:1 toluene-methanol mixture, with the alcohol employed being a crucial factor in terms of electronic and steric factors. A reaction mechanism involving a hydride addition–elimination mechanism starting with a palladium hydride species generated in situ in alcoholic solutions, as corroborated by experiments using deuterium labeled allylbenzene, seems to be most likely. The proposed mechanism is also supported by the observed reaction rate orders of κobs[cat.]≈1 (0.94), κobs [substrate]=0.20→1.0 (t→∞) and κobs [methanol]=−0.51 for the isomerization of allylbenzene. Furthermore, the influence of acid and base, as well as the role of the halide coordinated to the catalyst, are discussed. The system catalyzes the isomerization of allylbenzenes very efficiently yielding high E:Z selectivities under very mild conditions (room temperature) and at low catalyst loadings of 1 mol% palladium even in unpurified solvents. The integrity and stability of the catalyst system were confirmed by multiple addition reaction cycles, successive filtration and isolation experiments, and the lack of palladium black formation
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