Predicting reactivity for bioorthogonal cycloadditions involving nitrones

Nakajima, Masaya; Bilodeau, Didier A.; Pezacki, John Paul

doi:10.1039/d0ra05092j

Cited by 6 publications

(10 citation statements)

References 42 publications

(52 reference statements)

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“…Higher distortion energies were calculated for nitrone-dipolarophile transformations with later transition state geometries (close to final product geometries), while this trend only remained true for strained dipolarophile distortion energies . Calculated interaction energies were also found to display a linear free energy relationship with previously empirically determined second-order rate constants for reactions with cyclic nitrones . Overall, it was found that total interaction energies play a dominant role in affecting cycloaddition relative barrier heights and that these interaction energies determined via D/I analysis can be used to predict trends in reactivity and guide synthesis efforts for developing new bioorthogonal cycloaddition reactions …”

Section: Strain-promoted Alkyne-nitrone Cycloadditions (Spancs)mentioning

confidence: 62%

“…40 Calculated interaction energies were also found to display a linear free energy relationship with previously empirically determined secondorder rate constants for reactions with cyclic nitrones. 40 Overall, it was found that total interaction energies play a dominant role in affecting cycloaddition relative barrier heights and that these interaction energies determined via D/I analysis can be used to predict trends in reactivity and guide synthesis efforts for developing new bioorthogonal cycloaddition reactions. 40 2.4.…”

Section: Computational Distortion/interaction Analysis Of Bioorthogon...mentioning

confidence: 99%

“…40 Overall, it was found that total interaction energies play a dominant role in affecting cycloaddition relative barrier heights and that these interaction energies determined via D/I analysis can be used to predict trends in reactivity and guide synthesis efforts for developing new bioorthogonal cycloaddition reactions. 40 2.4. Applications in Biology 2.4.1.…”

Section: Computational Distortion/interaction Analysis Of Bioorthogon...mentioning

confidence: 99%

“…The activation barrier energies were in the range 13–23 kcal/mol, making them favorable transformations. Higher distortion energies were calculated for nitrone-dipolarophile transformations with later transition state geometries (close to final product geometries), while this trend only remained true for strained dipolarophile distortion energies . Calculated interaction energies were also found to display a linear free energy relationship with previously empirically determined second-order rate constants for reactions with cyclic nitrones .…”

Section: Strain-promoted Alkyne-nitrone Cycloadditions (Spancs)mentioning

confidence: 99%

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Bioorthogonal Reactions Utilizing Nitrones as Versatile Dipoles in Cycloaddition Reactions

et al. 2021

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Bioorthogonal chemical reactions have emerged as convenient and rapid methods for incorporating unnatural functionality into living systems. Different prototype reactions have been optimized for use in biological settings. Optimization of 3 + 2 dipolar cycloadditions involving nitrones has resulted in highly efficient reaction conditions for bioorthogonal chemistry. Through substitution at the nitrone carbon or nitrogen atom, stereoelectronic tuning of the reactivity of the dipole has assisted in optimizing reactivity. Nitrones have been shown to react rapidly with cyclooctynes with bimolecular rate constants approaching k 2 = 102 M–1 s–1, which are among the fastest bioorthogonal reactions reported (McKay et al. Org. Biomol. Chem. 2012, 10, 3066–3070). Nitrones have also been shown to react with trans-cyclooctenes (TCO) in strain-promoted TCO-nitrone cycloadditions reactions. Copper catalyzed reactions involving alkynes and nitrones have also been optimized for applications in biology. This review provides a comprehensive accounting of the different bioorthogonal reactions that have been developed using nitrones as versatile reactants, and provides some recent examples of applications for probing biological systems.

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Section: Strain-promoted Alkyne-nitrone Cycloadditions (Spancs)mentioning

confidence: 62%

Section: Computational Distortion/interaction Analysis Of Bioorthogon...mentioning

confidence: 99%

Section: Computational Distortion/interaction Analysis Of Bioorthogon...mentioning

confidence: 99%

Section: Strain-promoted Alkyne-nitrone Cycloadditions (Spancs)mentioning

confidence: 99%

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Bioorthogonal Reactions Utilizing Nitrones as Versatile Dipoles in Cycloaddition Reactions

et al. 2021

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“…These differences in orbital coefficients are likely to be similar for cycloadditions of nitrones with cyclooctadiynes. Recently, distortion/interaction energies have been highlighted as an important consideration for cycloadditions of cyclooctynes with various dipoles, including nitrones. − Given that distortion/interaction energies may play a more important role, we investigated the mechanistic possibilities further by conducting computational studies.…”

Section: Results and Discussionmentioning

confidence: 99%

Mechanistic Analysis of Bioorthogonal Double Strain-Promoted Alkyne–Nitrone Cycloadditions Involving Dibenzocyclooctadiyne

Bilodeau,

Margison,

Masoud

et al. 2023

ACS Chem. Biol.

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The reactions of nitrones with cyclooctadiynes were studied to establish the relative rates of sequential reactions and to determine the limits and scope of this bioorthogonal chemistry. We have established the second-order rate constants for the consecutive additions of a variety of nitrones onto diyne and studied the structure−activity relationships via Hammett plots. Results show that the addition of the second nitrone to the monointermediate occurs significantly faster than the first, with both reactions being faster than analogous reactions with azides. Computational chemistry supports these observations. The rate of second addition increases with electron-deficient nitrones, as demonstrated by a large rho value of 2.08, suggesting that the reaction rate can be controlled by nitrone selectivity. To further investigate the kinetic parameters of the reaction, dinitrone monomers containing cyclic and diaryl-nitrones were designed for use in oligomerization applications. Oligomerization was used as a probe to test the limits of the reactivity and attempt to isolate monocycloaddition products. The oligomer formed from a cyclic nitrone reacts faster, and detailed MALDI mass spectrometry analysis shows that monoaddition products exist only transiently and are not isolatable. These studies inform on the scope and limits of this chemistry in a variety of applications. We successfully demonstrated bacterial cell wall labeling using heterogeneous dual cycloadditions involving nitrone and azide dipoles, where the nitrone was the faster reacting partner on the bacterial cell surface.

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

Svatunek

2024

Top Curr Chem (Z)

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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.

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Predicting reactivity for bioorthogonal cycloadditions involving nitrones

Abstract: Nitrones are useful dipoles in both synthesis and in bioorthogonal transformations to report on biological phenomena.

Cited by 6 publications

References 42 publications

Bioorthogonal Reactions Utilizing Nitrones as Versatile Dipoles in Cycloaddition Reactions

Bioorthogonal Reactions Utilizing Nitrones as Versatile Dipoles in Cycloaddition Reactions

Mechanistic Analysis of Bioorthogonal Double Strain-Promoted Alkyne–Nitrone Cycloadditions Involving Dibenzocyclooctadiyne

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

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