Computational Organic Chemistry: The Frontier for Understanding and Designing Bioorthogonal Cycloadditions

Abstract

Computational organic chemistry has become a valuable tool in the field of bioorthogonal chemistry, offering insights and aiding in the progression of this branch of chemistry. In this review, I present an overview of computational work in this field, including an exploration of both the primary computational analysis methods used and their application in the main areas of bioorthogonal chemistry: (3 + 2) and [4 + 2] cycloadditions. In the context of (3 + 2) cycloadditions, detailed studies of electronic effects have informed the evolution of cycloalkyne/1,3-dipole cycloadditions. Through computational techniques, researchers have found ways to adjust the electronic structure via hyperconjugation to enhance reactions without compromising stability. For [4 + 2] cycloadditions, methods such as distortion/interaction analysis and energy decomposition analysis have been beneficial, leading to the development of bioorthogonal reactants with improved reactivity and the creation of orthogonal reaction pairs. To conclude, I touch upon the emerging fields of cheminformatics and machine learning, which promise to play a role in future reaction discovery and optimization.

Computational Large-Scale Screening of Bioorthogonal 1,2,4,5-Tetrazine/trans-Cyclooctene Cycloadditions

“…The kinetics of such reactions have been the focus of intensive investigation in numerous experimental and computational studies, aimed at understanding and improving reactivity. [5][6][7][8][9][10] Figure 1: Mechanism of the bioorthogonal 1,2,4,5-tetrazine/trans-cyclooctene reaction.…”