Monitoring of Organic Reactions with and without Accelerated Rates Using Electrospray and Ambient Ionization Mass Spectrometry

Ryan M Bain, Purdue University

Abstract

Charged microdroplets produced by spray-based ionization techniques such as electrospray ionization have been widely used as a means to probe both reaction mechanisms and kinetics. The same droplets have also been shown to allow increased chemical reactivity compared to corresponding bulk solution-phase kinetics. This apparent conundrum and the exploitation of droplet accelerated reactions were the foci of the work discussed in this dissertation. Controlling variables in the electrospray process as chemical as pH and concentration and as analytical as sheath gas flow and distance between the ion source and the ion transfer capillary of the mass spectrometer have allowed the selection between monitoring reactions by mass spectrometry with or without reaction rate acceleration. Many of these variables have been explored by the Cooks group, the Volmer group at Saarland University (Saarbrücken, Germany) and by the Zare group at Stanford University (Stanford, CA). The well-documented and empirically-backed theoretical models of electrospray ionization support the theories on the cause of reaction rate acceleration by spray-based processes. Using larger Leidenfrost droplets which are created by levitating reaction mixtures of superheated surfaces provides reaction acceleration as well with some similarities to electrospray droplets. Acoustically levitated droplets have also demonstrated the ability to accelerate reactions in small droplets and was used to probe the mechanism of this acceleration. Both adaptations of small volume reactors have potential for scale-up of these reactions and more efficient collections at the cost of lower rate enhancements compared to electrospray ionization processes. The applications of these accelerated reactions include the collection of organic product from the spray process, or more practically from Leidenfrost droplet experiments and screening of novel chemistry in droplets. Using the Leidenfrost experiment it was demonstrated that the synthesis of ca 18 mg of reaction product in the Katritzky pyrylium to pyridinium conversion could be achieved. This makes the Leidenfrost and other levitated droplet techniques an interesting option for scale-up of these accelerated reactions. On the other hand, the factors by which the reactions are accelerated and significantly reduced compared to related thin film and electrospray techniques. Reaction monitoring by electrospray ionization mass spectrometry is a very powerful tool for the investigation of homogeneous reaction mixtures both on-line and off-line. In a collaboration with Amgen Inc., the total synthesis of anagliptin was monitored on-line which provided information on byproducts and reaction completion as well as the ability to track starting materials that were not detectable by traditional methods. Additionally, in this Purdue-Amgen collaboration, a method of chiral analysis by mass spectrometry from reacting systems both off-line and on-line was developed and implemented on reaction systems of interest to Amgen (an enantioselective N-alkylation reaction and the base-catalyzed racemization of ibuprofen). Chiral analysis by mass spectrometry involves the creation of metal-coordinated diastereomeric cluster ions in the process of electrospray ionization which then can give rise to different abundances of product ions upon low-energy gas-phase dissociation of the isolated diastereomeric cluster ion. This method of chiral analysis by tandem mass spectrometry had been previously published but this was the first time this method had been applied to on-line or off-line reaction monitoring.

Degree

Ph.D.

Advisors

Cooks, Purdue University.

Subject Area

Chemistry|Analytical chemistry

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