autoDIAS: a python tool for an automated distortion/interaction activation strain analysis

Svatunek, Dennis; Houk, K. N.

doi:10.1002/jcc.26023

Cited by 35 publications

(30 citation statements)

References 47 publications

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“…The ASM can be applied to all unimolecular and bimolecular reactions in both homogeneous and heterogeneous systems and has been used routinely by theoretical and experimental chemists [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] . We provide specific examples of the ASM being applied to understand inorganic, organic, and supramolecular chemistries, namely, the transition metal-mediated oxidative addition of C-X bonds in cross-coupling reactions, the reactivity of cycloalkynes in 1,3-dipolar cycloadditions, the reactivity of dihalogen-catalyzed Michael addition reactions, and the bonding mechanism in hydrogen-bonded systems.…”

Section: Applications Of the Methodsmentioning

confidence: 99%

Understanding chemical reactivity using the activation strain model

et al. 2020

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Section: Applications Of the Methodsmentioning

confidence: 99%

Understanding chemical reactivity using the activation strain model

et al. 2020

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“…Frontier molecular orbitals were calculated on DFT-optimized structures at the HF level of theory with the 6-31G(d) basis set and visualized with Multiwfn and VMD . Fragment distortion and interaction energies were calculated with autoDIAS at the ωB97X-D level of theory with the aug-cc-pVTZ basis set in the gas phase. Energy decomposition analyses were performed in ADF 2019.304 at the ωB97X-D3/TZ2P level of theory using PyFrag 2019 .…”

Section: Methodsmentioning

confidence: 99%

Computational Exploration of Ambiphilic Reactivity of Azides and Sustmann’s Paradigmatic Parabola

Chen

Xue

et al. 2021

J. Org. Chem.

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We examine the theoretical underpinnings of the seminal discoveries by Reiner Sustmann about the ambiphilic nature of Huisgen’s phenyl azide cycloadditions. Density functional calculations with ωB97X-D and B2PLYP-D3 reproduce the experimental data and provide insights into ambiphilic control of reactivity. Distortion/interaction-activation strain and energy decomposition analyses show why Sustmann’s use of dipolarophile ionization potential is such a powerful predictor of reactivity. We add to Sustmann’s data set several modern distortion-accelerated dipolarophiles used in bioorthogonal chemistry to show how these fit into the orbital energy criteria that are often used to understand cycloaddition reactivity. We show why such a simple indicator of reactivity is a powerful predictor of reaction rates that are actually controlled by a combination of distortion energies, charge transfer, closed-shell repulsion, polarization, and electrostatic effects.

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“…3b) using the autoDIAS software package. 39 This energy decomposition method was introduced independently by Houk…”

Section: Resultsmentioning

confidence: 99%

Uncovering the key role of distortion in tetrazine ligations guides the design of bioorthogonal tools with high reactivity and superior stability

Svatunek

Wilkovitsch

Hartmann

et al. 2021

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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autoDIAS: a python tool for an automated distortion/interaction activation strain analysis

Cited by 35 publications

References 47 publications

Understanding chemical reactivity using the activation strain model

Understanding chemical reactivity using the activation strain model

Computational Exploration of Ambiphilic Reactivity of Azides and Sustmann’s Paradigmatic Parabola

Uncovering the key role of distortion in tetrazine ligations guides the design of bioorthogonal tools with high reactivity and superior stability

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