Novel analytical and preparative mass spectrometric methodologies in reaction monitoring and acceleration
Abstract
This dissertation explores two roles of limited volume solutions formed by dropcasting or by spray-based ionization processes in mass spectrometry, 1) as microcontainers to allow monitoring of bulk reactions or 2) as microreactors in which to accelerate reactions. Droplets derived from the bulk reaction phase can be used to monitor the reactions. An inductive electrospray mass spectrometry (iESI-MS)-based reaction monitoring system was built to use charged droplets emitted in the electric field of a pulsed DC potential to track chemical reactions in real time, including air and moisture-sensitive and heterogeneous reactions. Highly concentrated solutions can be monitored for long periods without the spray emitter clogging. Sheath gas assists in nebulization and a sample splitter reduces the delay time and minimizes contamination of the instrument. We applied this system in both a mechanistic study of Negishi cross-coupling of 3-bromoquinoline with diethylzinc and in Pd/C-catalyzed hydrogenolysis of 3,4-dimethoxy-benzaldehyde, as well as in process control of the synthetic route to an active pharmaceutical ingredient (API). The MS reaction monitoring system was further enhanced by an on-line quantitation device which allows the introduction of internal standards accurately without affecting the reaction or later product separation. It also allows dilution of aliquots of the reaction solution to different extents, so that the concentration of each analyte falls within the linear dynamic range (LDR), and it thus can be easily quantified. The reaction of L-arginine with N-(Cbz-isopropyl-aminoacyl)-benzotriazole to yield dipeptide Cbz-L-Val-L-Arg was successfully quantified using this system while its reaction kinetics were explored also. Droplets formed by paper spray MS were also used to evaluate enzyme activity by following the product formation of an enzymatic reaction. A simple MS protocol was developed for evaluation of enzymatic activity using few reagents and without sample pretreatment or derivatization reactions (which is commonly used in other methods). In contrast to their role as simple microcontainers, droplets have been found a new role in reaction acceleration compared to the bulk phase. Droplets formed by dropcasting/spray-based ionization mass spectrometry can act as microreactors in which the reactions run much faster than those in the bulk solution. Droplet reaction acceleration also extends to thin film reactions as was performed in the reactive paper spray experiment which represents an alternative version of limited-volume reactors. The Katritzky reaction between a pyrylium salt and mono- or di-amines, including substituted anilines, is an example that was investigated by reactive paper spray. The increase in rate of product formation is attributed to solvent evaporation which increases reagent concentrations, to changes the pH and to enhanced intermolecular interactions at the interface. Droplet acceleration is promising for preparative scale synthesis on a short timescale. It might open a new dimension in the field of synthetic organic chemistry.
Degree
Ph.D.
Advisors
Cooks, Purdue University.
Subject Area
Analytical chemistry|Organic chemistry
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