Low-cost, automated reaction screening for energetic precursor cage compounds by a benchtop liquid handling robot and desorption electrospray ionization mass spectrometry

High-throughput reaction screening by mass spectrometry (MS) enables detection of multiple analytes simultaneously without tagging, permitting the starting materials, intermediates, and products to be detected and identified concurrently. Presented here, desorption electrospray ionization (DESI) was coupled with MS to accelerate and screen the formation of highly desired precursors to energetic cage compounds structurally similar to 2,4,6,8,10,12-hexabenzyl-2,4,6,8,10,12-hexaazaisowurtzitane (HBIW) with a variety of amine analogs and acid catalysts. Organic reactions are accelerated in the microdroplets generated from the DESI source, due to the evaporation of solvent, the increase in reagent concentration, and higher surface-to-volume ratios, amongst other phenomena. To increase the throughput and create reproducible reaction spots, a low-cost commercial-off-the-shelf automated pipetting robot was used to prepare and spot the reaction solutions. Once spotted, the reaction mixtures were analyzed using a low-cost and homebuilt DESI stage coupled to a linear ion trap MS. The expected cage products, HBIW and analogous cages, were successfully formed using benzylamine, bromo-benzylamine, and methoxy-benzylamine as the amine starting material, demonstrating this budget-friendly setup as a rapid and high-throughput screening setup for exploring alternative complex cage structures. Several acids were also screened for alternative acid catalyst options. Compared to other expensive automated pipetting systems and DESI setups, this design has reduced throughput (6000 vs. 100 samples per hour), but it provides a budget-friendly, open-source option.