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

TL;DR

This study uses an automated workflow to compute over 5000 reaction profiles for [3 + 2] cycloadditions, aiding the discovery of bio-orthogonal click reactions and advancing reaction prediction methods.

Contribution

Introduces a high-throughput computational workflow for reaction profile analysis of [3 + 2] cycloadditions under physiological conditions.

Findings

Identified suitable computational methods for reaction profiling.

Generated extensive reaction data for bio-orthogonal chemistry.

Provided a tool for screening new bio-orthogonal reactions.

Abstract

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.