Influence of intramolecular interactions and transition state energetics on the strain-promoted azide–alkyne cycloaddition of 2-aminobenzenesulfonamide-containing cyclononynes

TL;DR

This paper studies how molecular interactions and energy differences affect a specific chemical reaction involving cyclononyne compounds.

Contribution

The study reveals how intramolecular hydrogen bonds and transition state energetics influence reaction selectivity in strain-promoted cycloadditions.

Findings

The reaction pathway is determined by the most energetically favorable route, minimizing steric and strain effects.

Intramolecular hydrogen bonds are preserved in transition states for Boc-protected cyclononyne, matching experimental results.

Calculated product ratios align with experimental data, confirming the role of hydrogen bonding in selectivity.

Abstract

Computational investigation of the reaction mechanism and selectivity of strain-promoted azide–alkyne cycloaddition indicated that 2-aminobenzenesulfonamide-containing cyclononyne (ABSACN) is a HOMO donor; the energy difference is slight between the transition states (TSs) for the major and minor products. The reaction between unsubstituted ABSACN(R1

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R2H) and benzyl azide proceeds via the pathway that is most energetically favorable, minimizing the influence of steric repulsion, intermolecular interactions, and the strain energy of ABSACN. In the case of R1Boc, the intramolecular hydrogen bond is maintained in both the X-ray-characterized minor product and its corresponding transition state, and the calculated product ratios coincided with the experimental data.

When a Boc-protected cyclononyne reacts, intramolecular hydrogen bonds are retained in the transition state. The calculated product ratios align with experimental findings.

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