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Automating reaction discovery

Approach combines chemical design and informatics to find new chemical transformations

by Bethany Halford
July 13, 2017 | A version of this story appeared in Volume 95, Issue 29

Scheme showing a three-component, nickel-catalyzed diarylation of alkynes.
UC Berkeley chemists discovered this three-component, nickel-catalyzed diarylation of alkynes using an automated reaction discovery process.

When hunting for novel chemical reactions, the more transformations chemists can do, the more likely they are to find something new. University of California, Berkeley, chemists John F. Hartwig and Konstantin Troshin have come up with an approach that lets reaction hunters run 75,000 possible reactions in just a matter of days using only a sealed 96-well plate, a gas chromatography/mass spectrometry instrument, and an analytical suite of Microsoft Excel macros (Science 2017, DOI: 10.1126/science.aan1568).

The reaction discovery method updates an earlier approach taken by Hartwig’s lab, in which the chemists loaded a combination of 17 reactants into each well of a 96-well plate and then added a different metal and ligand combination to each. They then used GC/MS to analyze their results (C&EN, Sept. 12, 2011, page 10).

“The deconvolution of the GC/MS data to identify more than the major products was a stumbling block for the routine use of this approach,” Hartwig says. So he and Troshin went back to the drawing board.

Their new method uses three pools of compounds. Each pool has molecules with the same types of functional groups: an alkyne, a halide, and a boronic acid, for example. The pools differ in that the compounds also have inert substituents that vary in mass. So when the compounds react, they form products with unique differences in mass that are easily detected by GC/MS and identified by analysis with the macros.

“The design and implementation is complex, but the outcome is simple,” Hartwig says. “By following these macros, the outcomes of thousands of possible reactions of two or multiple reactants can be analyzed in an automated fashion, and new reactions can be discovered.”

“This is a real breakthrough, since it speeds up the time for analysis and allows its automation,” comments Frank Glorius, an expert on smart screening approaches in organic chemistry at the University of Münster. He notes that Hartwig and Troshin even managed to use the method to discover a previously unknown nickel-catalyzed, three-component reaction. “This paper will attract a lot of interest from chemists from different disciplines, leading to more activity in this challenging field of ‘smart screening,’ ” Glorius says.



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