autoDIAS: A Python Tool for an Automated Distortion/Interaction Activation Strain Analysis

Svatunek, Dennis; Houk, K. N.

doi:10.26434/chemrxiv.7789940.v2

Cited by 2 publications

(2 citation statements)

References 31 publications

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“…3b) using the autoDIAS software package. [39] This energy decomposition method was introduced independently by Houk and Bickelhaupt and has successfully been applied to investigate bioorthogonal cycloadditions. [32,[40][41][42] In this analysis, the energy of activation (ΔE ‡ ) is dissected into two parts, the distortion energy (ΔEdist), which is needed to distort the isolated reactants into transition state geometry, and the interaction energy (ΔEint) resulting from bringing the two distorted isolated fragments together.…”

Section: Resultsmentioning

confidence: 99%

Uncovering the key role of distortion in tetrazine ligations guides the design of bioorthogonal tools that defy the reactivity/stability tradeoff

Svatunek

Wilkovitsch

Hartmann

et al. 2022

Preprint

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The tetrazine/trans-cyclooctene ligation stands out from the bioorthogonal toolbox due to its exceptional reaction kinetics, enabling multiple molecular technologies in vitro and in living systems. Highly reactive 2-pyridyl-substituted tetrazines have become state-of-the-art for time-critical processes and selective reactions at very low concentration. It is widely accepted that the enhanced reactivity of these chemical tools is attributed to the electron-withdrawing effect of the heteroaryl substituent. In contrast, we show that observed reaction rates are way too high to be explained on this basis. Computational investigation of this phenomenon revealed that distortion of the tetrazine caused by intramolecular N-N repulsion plays a key role in accelerating the cycloaddition step. While we show that the limited stability of tetrazines under physiological conditions strongly correlates with the electron-withdrawing effect of the substituent, intramolecular destabilization increases the reactivity without reducing stability. Guided by these fundamental insights we demonstrate application in the design of highly reactive tetrazines with superior stability, finally evading the reactivity/stability trade-off for bioorthogonal tetrazine tools.

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Section: Resultsmentioning

confidence: 99%

Uncovering the key role of distortion in tetrazine ligations guides the design of bioorthogonal tools that defy the reactivity/stability tradeoff

Svatunek

Wilkovitsch

Hartmann

et al. 2022

Preprint

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“…Preparation of structures for the ASM analysis along the IRC was carried out with the help of the autoDIAS program by Svatunek and Houk. 52 On the other hand, the polarization components of 𝐽(𝜉) were determined through counterpoise calculations 44,53 of molecular fragments using the geometry they would have within the supermolecule at every point along the IRC.…”

Section: Computational Detailsmentioning

confidence: 99%

Digging on the Mechanism of Some Diels-Alder Reactions. The Role of the Reaction Electronic Flux

Hernández-Mancera

Vivas‐Reyes

Gutiérrez‐Oliva

et al. 2023

Preprint

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Within the framework of the reaction force analysis, the Marcus Potential Energy Function as well as the Activation Strain Model are characterized and used to rationalize the energetics of some representative Diels-Alder reactions involving three substituted furandione as dienophile, and a chiral anthracene, as diene. The analysis of reaction barriers indicates that the activation process of the reactions is dominated by the structural rearrangements of reactants which are mainly driven by the approach of diene to the dienophile. On the other hand, the electronic activity taking place along the reaction coordinate have been analyzed through the reaction electronic flux. It has been found that the electronic activity that emerge more intensively within the transition state region, is mainly due to electronic transfer effects, due to the breaking and forming π bonds. Although polarization is also present but to a lesser extent.

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autoDIAS: A Python Tool for an Automated Distortion/Interaction Activation Strain Analysis

Cited by 2 publications

References 31 publications

Uncovering the key role of distortion in tetrazine ligations guides the design of bioorthogonal tools that defy the reactivity/stability tradeoff

Uncovering the key role of distortion in tetrazine ligations guides the design of bioorthogonal tools that defy the reactivity/stability tradeoff

Digging on the Mechanism of Some Diels-Alder Reactions. The Role of the Reaction Electronic Flux

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