HIGH-THROUGHPUT ORGANIC REACTION SCREENING USING DESORPTION ELECTROSPRAY IONIZATION MASS SPECTROMETRY

2019-12-06T15:25:35Z (GMT) by David L Logsdon
This dissertation describes the development of a system for the automated, high-throughput screening of organic reactions. This system utilizes a liquid handling robot for reaction mixture preparation combined with desorption electrospray ionization mass spectrometry (DESI-MS) for reaction mixture analysis. With an analysis speed of ~1 second per reaction mixture, this system is capable of screening thousands of reactions per hour. Reaction mixtures are prepared in 384-well microtiter plates using a liquid handling robot. A sample of each reaction mixture (50 nL) is then transferred to a PTFE coated, glass slide using a pin tool. By offsetting the placement of the pin tool during each transfer, up to 6,144 unique reaction mixtures can be placed on each slide. The slide is then transferred to the DESI stage by a robotic arm, and the DESI-MS analysis begins, taking as little as 7 minutes for 384 reaction mixtures. We utilize a scheduling software to control each component of the system, which automates the entire process from reaction mixture preparation to DESI-MS analysis. In order to efficiently analyze and visualize the extremely large data sets generated by the system, we developed a custom software suite to automatically process each data set. We have used this system to screen several classes of industrially relevant reactions including Suzuki coupling, nucleophilic aromatic substitution, reductive amination, and Sonogashira coupling. We have validated both positive and negative results from the system using flow chemistry, and we have observed excellent agreement between the two methodologies. By being capable of screening thousands of reactions per hour, requiring only microliter quantities of reaction mixtures, and consuming less than a milliliter of solvent during the DESI-MS analysis, this system significantly reduces the time and costs associated with organic reaction screening.