Reaction profiles for quantum chemistry-computed [3+2] cycloaddition reactions

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.

Automated summary

Bio-orthogonal click chemistry has had a significant impact on biochemistry, and identifying new candidate reactions is crucial. This study used an automated workflow to compute over 5000 reaction profiles for [3 + 2] cycloadditions, providing valuable information for screening and predicting chemical reactivity. The B3LYP-D3(BJ)/def2-TZVP//B3LYP-D3(BJ)/def2-SVP level of theory was selected for the calculations, and standard conditions and a SMD model were used to mimic physiological conditions.