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Reactivity of biarylazacyclooctynones in copper-free click chemistry.

Gordon CG, Mackey JL, Jewett JC, Sletten EM, Houk KN, Bertozzi CR - J. Am. Chem. Soc. (2012)

Bottom Line: Experimental data confirmed that electronic perturbation of BARAC's aryl rings has a modest effect on reaction rate, whereas steric hindrance in the transition state can significantly retard the reaction.Drawing on these results, we analyzed the relationship between alkyne bond angles, which we determined using X-ray crystallography, and reactivity, quantified by experimental second-order rate constants, for a range of cyclooctynes.Our results suggest a correlation between decreased alkyne bond angle and increased cyclooctyne reactivity.

View Article: PubMed Central - PubMed

Affiliation: Departments of Chemistry, University of California - Berkeley, 94720, United States.

ABSTRACT
The 1,3-dipolar cycloaddition of cyclooctynes with azides, also called "copper-free click chemistry", is a bioorthogonal reaction with widespread applications in biological discovery. The kinetics of this reaction are of paramount importance for studies of dynamic processes, particularly in living subjects. Here we performed a systematic analysis of the effects of strain and electronics on the reactivity of cyclooctynes with azides through both experimental measurements and computational studies using a density functional theory (DFT) distortion/interaction transition state model. In particular, we focused on biarylazacyclooctynone (BARAC) because it reacts with azides faster than any other reported cyclooctyne and its modular synthesis facilitated rapid access to analogues. We found that substituents on BARAC's aryl rings can alter the calculated transition state interaction energy of the cycloaddition through electronic effects or the calculated distortion energy through steric effects. Experimental data confirmed that electronic perturbation of BARAC's aryl rings has a modest effect on reaction rate, whereas steric hindrance in the transition state can significantly retard the reaction. Drawing on these results, we analyzed the relationship between alkyne bond angles, which we determined using X-ray crystallography, and reactivity, quantified by experimental second-order rate constants, for a range of cyclooctynes. Our results suggest a correlation between decreased alkyne bond angle and increased cyclooctyne reactivity. Finally, we obtained structural and computational data that revealed the relationship between the conformation of BARAC's central lactam and compound reactivity. Collectively, these results indicate that the distortion/interaction model combined with bond angle analysis will enable predictions of cyclooctyne reactivity and the rational design of new reagents for copper-free click chemistry.

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Distortion/interactionmodel. (a) Activation energy (ΔE⧧) for the reaction between 2-butyneand methyl azide is the sum of distortion energy (ΔE⧧d) and interaction energy (ΔE⧧i). (b) Perfluorination ofthe alkyne reduces ΔE⧧ ofthe reaction by increasing the magnitude of stabilizing interactionsin the transition state and decreasing distortion energy. (c) Constrainingthe alkyne into an eight-membered ring reduces ΔE⧧ by decreasing the distortion energy requiredto bend the starting materials into their preferred transition stateconformations. For a–c, calculated values are electronic energies,the potential energy of the molecule on a vibrationless potentialenergy surface. As all reactions are represented on separate energydiagrams, the depictions are only intended to facilitate comparisonsof ΔE⧧, ΔE⧧d, and ΔE⧧i values and not the overall energies ofstarting materials or triazole products. Calculations were performedusing B3LYP/6-31G(d). See Supporting Information for details.
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fig2: Distortion/interactionmodel. (a) Activation energy (ΔE⧧) for the reaction between 2-butyneand methyl azide is the sum of distortion energy (ΔE⧧d) and interaction energy (ΔE⧧i). (b) Perfluorination ofthe alkyne reduces ΔE⧧ ofthe reaction by increasing the magnitude of stabilizing interactionsin the transition state and decreasing distortion energy. (c) Constrainingthe alkyne into an eight-membered ring reduces ΔE⧧ by decreasing the distortion energy requiredto bend the starting materials into their preferred transition stateconformations. For a–c, calculated values are electronic energies,the potential energy of the molecule on a vibrationless potentialenergy surface. As all reactions are represented on separate energydiagrams, the depictions are only intended to facilitate comparisonsof ΔE⧧, ΔE⧧d, and ΔE⧧i values and not the overall energies ofstarting materials or triazole products. Calculations were performedusing B3LYP/6-31G(d). See Supporting Information for details.

Mentions: In the case of the 1,3-dipolar cycloadditionof 2-butyne with methylazide (Figure 2a), our calculations indicatethat 29.9 kcal/mol energy is required to distort the ground statesubstrates into their preferred transition state conformations. Upondistortion, the alkyne and azide interact, lowering the energy ofthe overall system by −9.0 kcal/mol through a favorable orbitaloverlap that can only be achieved via the geometry of the distortedstate. Combining the effects of distortion and interaction, we calculatean overall transition state activation energy of 20.9 kcal/mol (ΔE⧧ = ΔE⧧d + ΔE⧧i). In reality, distortion and interaction are not independent processesbut instead occur simultaneously to bring reactants directly to theirtransition state geometries. However, this model breaks up activationenergy into two imaginary distortion and interaction processes toallow a more detailed analysis of reaction strain and electronics.


Reactivity of biarylazacyclooctynones in copper-free click chemistry.

Gordon CG, Mackey JL, Jewett JC, Sletten EM, Houk KN, Bertozzi CR - J. Am. Chem. Soc. (2012)

Distortion/interactionmodel. (a) Activation energy (ΔE⧧) for the reaction between 2-butyneand methyl azide is the sum of distortion energy (ΔE⧧d) and interaction energy (ΔE⧧i). (b) Perfluorination ofthe alkyne reduces ΔE⧧ ofthe reaction by increasing the magnitude of stabilizing interactionsin the transition state and decreasing distortion energy. (c) Constrainingthe alkyne into an eight-membered ring reduces ΔE⧧ by decreasing the distortion energy requiredto bend the starting materials into their preferred transition stateconformations. For a–c, calculated values are electronic energies,the potential energy of the molecule on a vibrationless potentialenergy surface. As all reactions are represented on separate energydiagrams, the depictions are only intended to facilitate comparisonsof ΔE⧧, ΔE⧧d, and ΔE⧧i values and not the overall energies ofstarting materials or triazole products. Calculations were performedusing B3LYP/6-31G(d). See Supporting Information for details.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368396&req=5

fig2: Distortion/interactionmodel. (a) Activation energy (ΔE⧧) for the reaction between 2-butyneand methyl azide is the sum of distortion energy (ΔE⧧d) and interaction energy (ΔE⧧i). (b) Perfluorination ofthe alkyne reduces ΔE⧧ ofthe reaction by increasing the magnitude of stabilizing interactionsin the transition state and decreasing distortion energy. (c) Constrainingthe alkyne into an eight-membered ring reduces ΔE⧧ by decreasing the distortion energy requiredto bend the starting materials into their preferred transition stateconformations. For a–c, calculated values are electronic energies,the potential energy of the molecule on a vibrationless potentialenergy surface. As all reactions are represented on separate energydiagrams, the depictions are only intended to facilitate comparisonsof ΔE⧧, ΔE⧧d, and ΔE⧧i values and not the overall energies ofstarting materials or triazole products. Calculations were performedusing B3LYP/6-31G(d). See Supporting Information for details.
Mentions: In the case of the 1,3-dipolar cycloadditionof 2-butyne with methylazide (Figure 2a), our calculations indicatethat 29.9 kcal/mol energy is required to distort the ground statesubstrates into their preferred transition state conformations. Upondistortion, the alkyne and azide interact, lowering the energy ofthe overall system by −9.0 kcal/mol through a favorable orbitaloverlap that can only be achieved via the geometry of the distortedstate. Combining the effects of distortion and interaction, we calculatean overall transition state activation energy of 20.9 kcal/mol (ΔE⧧ = ΔE⧧d + ΔE⧧i). In reality, distortion and interaction are not independent processesbut instead occur simultaneously to bring reactants directly to theirtransition state geometries. However, this model breaks up activationenergy into two imaginary distortion and interaction processes toallow a more detailed analysis of reaction strain and electronics.

Bottom Line: Experimental data confirmed that electronic perturbation of BARAC's aryl rings has a modest effect on reaction rate, whereas steric hindrance in the transition state can significantly retard the reaction.Drawing on these results, we analyzed the relationship between alkyne bond angles, which we determined using X-ray crystallography, and reactivity, quantified by experimental second-order rate constants, for a range of cyclooctynes.Our results suggest a correlation between decreased alkyne bond angle and increased cyclooctyne reactivity.

View Article: PubMed Central - PubMed

Affiliation: Departments of Chemistry, University of California - Berkeley, 94720, United States.

ABSTRACT
The 1,3-dipolar cycloaddition of cyclooctynes with azides, also called "copper-free click chemistry", is a bioorthogonal reaction with widespread applications in biological discovery. The kinetics of this reaction are of paramount importance for studies of dynamic processes, particularly in living subjects. Here we performed a systematic analysis of the effects of strain and electronics on the reactivity of cyclooctynes with azides through both experimental measurements and computational studies using a density functional theory (DFT) distortion/interaction transition state model. In particular, we focused on biarylazacyclooctynone (BARAC) because it reacts with azides faster than any other reported cyclooctyne and its modular synthesis facilitated rapid access to analogues. We found that substituents on BARAC's aryl rings can alter the calculated transition state interaction energy of the cycloaddition through electronic effects or the calculated distortion energy through steric effects. Experimental data confirmed that electronic perturbation of BARAC's aryl rings has a modest effect on reaction rate, whereas steric hindrance in the transition state can significantly retard the reaction. Drawing on these results, we analyzed the relationship between alkyne bond angles, which we determined using X-ray crystallography, and reactivity, quantified by experimental second-order rate constants, for a range of cyclooctynes. Our results suggest a correlation between decreased alkyne bond angle and increased cyclooctyne reactivity. Finally, we obtained structural and computational data that revealed the relationship between the conformation of BARAC's central lactam and compound reactivity. Collectively, these results indicate that the distortion/interaction model combined with bond angle analysis will enable predictions of cyclooctyne reactivity and the rational design of new reagents for copper-free click chemistry.

Show MeSH
Related in: MedlinePlus