Implementation of a novel method for high-throughput screening of reactions in microdroplets. The reaction and analysis steps are performed simultaneously using desorption electrospray ionization mass spectrometry (DESI-MS) at a rate of up to 1 reaction mixture per second.
This study describes the latest generation
of a high-throughput
screening system that is capable of screening thousands of organic
reactions in a single day. This system combines a liquid handling
robot with desorption electrospray ionization (DESI) mass spectrometry
(MS) for a rapid reaction mixture preparation, accelerated synthesis,
and automated MS analysis. A total of 3840 unique reductive amination
reactions were screened to demonstrate the throughputs that are capable
with the system. Products, byproducts, and intermediates were all
monitored in full-scan mass spectra, generating a complete view of
the reaction progress. Tandem mass spectrometry experiments were conducted
to verify the identity of the products formed. The amine and electrophile
reactivity trends represented in the data match what is expected from
theory, indicating that the system accurately models the reaction
performance. The DESI results correlated well with those generated
using more traditional mass spectrometry techniques like liquid chromatography–mass
spectrometry, validating the data generated by the system.
Nucleophilic aromatic
substitution (SNAr) reactions were optimized using high-throughput
experimentation techniques for execution under flow conditions. A
total of 3072 unique reactions were evaluated with an analysis time
of ∼3.5 s per reaction using a system that combines a liquid
handling robot for reaction mixture preparation with desorption electrospray
ionization (DESI) mass spectrometry (MS) for analysis. The reactions
were performed in bulk microtiter arrays with and without incubation.
In-house developed software was used to process the data and generate
heat maps of the results. This information was then used to select
the most promising conditions for continuous synthesis under microfluidic
reactor conditions. Our results show that this HTE approach provides
robust guidance for narrowing the range of conditions needed for optimization
of SNAr reactions.
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