Data-Driven Identification of Metal-free Orthogonal Bioorthogonal Cycloaddition Pairs

24 January 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Mutually orthogonal bioorthogonal reactions are a thriving area of research in chemical biology. Here we present a predictive-driven approach to identify mutually orthogonal pairs among two bioorthogonal reactions: the metal-free 1,3-dipolar cycloaddition (1,3-DC) reaction and the inverse electron-demand Diels–Alder (IEDDA) reaction. Parametrization of both 1,3-dipoles and dipolarophiles structures allowed the development of statistically robust models for predicting the second order rate constants of 1,3-DC reactions. Combination of predictive models were used to identify potential mutually orthogonal reactions among sets of structurally different pairs.


Reaction rates
Bioorthogonal cycloadditions
Chemical structures
Density Functional Theory
Statistical Analysis

Supplementary materials

Supporting Information
Computational methods


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