Fig. 1. Nanomole-scale reaction screening. (A) High-complexity electrophilic
cores 1 to 8 from the Merck compound collection. (B) High-polarity nucleophilic building blocks 9 to 20. (C) Route scouting to identify successful reaction
conditions for previously failed chemistry can be accomplished using nanomole-scale reaction screening with minimal consumption of precious substrate
(0.02 mg per reaction). Successful reactions run on nanoscale (0.02 mg,
50 nmol) can be repeated on a 25-mg scale (factor of 1000 scale-up). A 96-
member parallel coupling library using best reaction conditions located by
screening model nucleophiles (table S3) gave 54 products (white squares) and
42 failed reactions (blue squares) (table S4). After nanomole-scale screening,
productive conditions were located for an additional 21 of the 96 products
(yellow squares) (tables S6 and S8). (D) Reaction mixtures that are fully soluble in high-boiling solvents can be dosed with high-precision nanoliter robotics.
Room-temperature reactions require no stirring and minimal sealing. (E) High-performance LC-MS MISER analysis allows for rapid label-free analysis of reactions with diverse products. (F) Reaction discovery: Organic superbases 24
to 29 promote room-temperature cross-coupling in DMSO with second- and
third-generation biaryl palladium precatalysts 30 to 45. (G) Ninety-six combinations of bases and ligands were investigated in triplicate in glass microvials
with stirring and reproduced in 1536-well plastic microtiter plates without stirring.