Optimization of information content in a mass spectrometry based flow-chemistry system by investigating different ionization approaches.

Current development in catalyst discovery includes combinatorial synthesis methods for the rapid generation of compound libraries combined with high-throughput performance-screening methods to determine the associated activities. Of these novel methodologies, mass spectrometry (MS) based flow chemistry methods are especially attractive due to the ability to combine sensitive detection of the formed reaction product with identification of introduced catalyst complexes. Recently, such a mass spectrometry based continuous-flow reaction detection system was utilized to screen silver-adducted ferrocenyl bidentate catalyst complexes for activity in a multicomponent synthesis of a substituted 2-imidazoline. Here, we determine the merits of different ionization approaches by studying the combination of sensitive detection of product formation in the continuous-flow system with the ability to simultaneous characterize the introduced [ferrocenyl bidentate+Ag](+) catalyst complexes. To this end, we study the ionization characteristics of electrospray ionization (ESI), atmospheric-pressure chemical ionization (APCI), no-discharge APCI, dual ESI/APCI, and dual APCI/no-discharge APCI. Finally, we investigated the application potential of the different ionization approaches by the investigation of ferrocenyl bidentate catalyst complex responses in different solvents.

Tandem mass spectrometry of silver-adducted ferrocenyl catalyst complexes.

Ferrocene is a popular template in material science due to its exceptional characteristics that offer the ability to optimize the selectivity and activity of catalysts by the addition of carefully selected substituents. In combinatorial catalyst development, the high susceptibility to electrophilic substitution reactions offers the opportunity for the rapid introduction of molecular diversity. Mass spectrometry (MS)-based continuous-flow systems can be applied to rapidly evaluate catalyst performance as well as to (provisionally) identify the introduced catalyst complexes. Herein, we describe the fragmentation characteristics of the [ferrocenyl bidentate + Ag](+) catalyst complexes in dedicated (high-resolution) MS(n) experiments. The investigation of the fragmentation patterns of a selected number of catalyst classes is accompanied with a density functional theory investigation of fragmentation intermediates in order to assess the viability of a selected fragmentation mechanism.

High-throughput reaction optimisation and activity screening of ferrocene-based Lewis acid-catalyst complexes by using continuous-flow reaction detection mass spectrometry.

Optimising synthetic conversions and assessing catalyst performance is a tedious and laborious endeavour. Herein, we present an automated alternative to the commonly applied sequential approaches that are used to increase catalyst discovery process efficiencies by increasing the number of entities that can be tested. This new approach combines conversion of the reactants and determination of product formation into a single comprehensive reaction detection system that can be operated with minimal catalyst and reactant consumption. With this approach, rudimentary reaction conditions can be quickly optimised and the same system can then be used to screen for the optimal homogenous catalyst in a selected solution-phase synthetic conversion. The system, which is composed of standard HPLC components, can be used to screen catalyst libraries at a repetition rate of five minutes and can be run unsupervised. The sensitive mass spectrometric detection that is implemented in the reaction detection methodology can be used for the simultaneous monitoring of reactants, catalysts and product ions. In the experiments, the three-component reaction that gives a substituted 2-imidazoline was optimised. Afterwards, the same method was used to assess a library of ferrocene-based Lewis acid catalysts for performance in the aforementioned conversion in six different solvents. We demonstrate the feasibility of using this methodology to directly compare the performance results obtained in different solvents by calibrating the solvent-specific MS responses.

Online screening of homogeneous catalyst performance using reaction detection mass spectrometry.

An integrated online screening system was developed to rapidly screen homogeneous catalysts for activity toward a selected synthesis. The continuous-flow system comprises standard HPLC pumps for the delivery of substrates, an HPLC autosampler for the injection of homogeneous catalysts, a thermostated reactor to mediate synthesis, and a single-stage quadrupole mass spectrometer (MS) equipped with atmospheric pressure chemical ionization for the determination of product formation. MS detection offers sensitivity, specificity, and speed when applied to the analysis of dynamic processes in the condensed phase. By applying the present methodology for the study of substrate conversion mediated by homogeneous catalysts, the concentration of substrates and reaction product could be monitored while information about the catalysts could also be obtained. In an initial screening application, the performance of a selected number of Lewis acids in the multicomponent synthesis of a highly substituted 2-imidazoline was determined. Limit of detection and limit of quantitation were determined by injecting different concentrations of 2-imidazoline standards and proved to be 1.6 and 5.2 nM, respectively. The results obtained with the new screening method were in good agreement with a traditional bench-scale experiment. Moreover, the system was capable of determining catalyst performance with very low catalyst and solvent consumption while the ruggedness of the system was exhibited with a 24-h continuous analysis of 280 successive catalyst injections with a peak area variation within 7% relative standard deviation.

Sensitive determination of G-protein-coupled receptor binding ligands by solid phase extraction-electrospray ionization-mass spectrometry.

High affinity Histamine H2-receptor binding ligands were assayed by automated solid phase extraction (SPE) coupled via electrospray ionization with a Quadrupole-Time-of-Flight mass spectrometer (Q-ToF-MS). The mass spectrometric behavior of these analytes was tested in aqueous solutions with several (nine) volatile salts, in different pH, and with various methanol contents. Out of the high amount of available ligands, three fluorescent-labeled molecules (5706, 5707, and 5708) were studied in detail. The limits of detection (LODs) for all three compounds obtained in mass spectrometric detection was 1 fmol (absolute) in continuous flow and FIA (flow injection analysis) measurements. The results obtained with FIA-fluorescence detection gave LODs a factor 10-100 times higher. A systematic investigation of sample solving conditions, loading flow conditions, and elution flow conditions made the automated SPE-MS coupling efficient. Ideally, the ligands were dissolved in MeOH-25 mM phosphate buffer (30:70 v/v; pH 11), the SPE loading flow comprised MeOH-25 mM phosphate buffer (30:70 v/v; pH 11) and the SPE elution flow contained MeOH-100 mM ammonium formate solution (90:10 v/v; pH 3). Using this method on a C18-modified silica cartridge (C18, 5 microm, 100 A, 300 microm i.d. x 5 mm, LC Packings) assures high recovery and achieved LODs for all three compounds of 5 fmol (absolute). As an absolute amount of ligands specifically bound on H2-receptors in biochemical experiments is, as will be published elsewhere, between 10 and 100 fmol, the SPE-MS method for the basic compounds can be directly applied for these Histamine H2-receptors.