  Bio-orthogonal click chemistry based on [3 + 2] dipolar cycloadditions has
had a profound impact on the field of biochemistry and significant effort has
been devoted to identify promising new candidate reactions for this purpose. To
gauge whether a prospective reaction could be a suitable bio-orthogonal click
reaction, information about both on- and off-target activation and reaction
energies is highly valuable. Here, we use an automated workflow, based on the
autodE program, to compute over 5000 reaction profiles for [3 + 2]
cycloadditions involving both synthetic dipolarophiles and a set of
biologically-inspired structural motifs. Based on a succinct benchmarking
study, the B3LYP-D3(BJ)/def2-TZVP//B3LYP-D3(BJ)/def2-SVP level of theory was
selected for the DFT calculations, and standard conditions and an (aqueous) SMD
model were imposed to mimic physiological conditions. We believe that this
data, as well as the presented workflow for high-throughput reaction profile
computation, will be useful to screen for new bio-orthogonal reactions, as well
as for the development of novel machine learning models for the prediction of
chemical reactivity more broadly.
