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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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Related in: MedlinePlus

Reagent development for copper-free click chemistry. (a) The 1,3-dipolarcycloaddition between azides and cyclooctynes. (b) Oct, the firstcyclooctyne developed as a bioorthogonal reagent, and its correspondingsecond-order rate constant for the reaction with benzyl azide.5,6 The reactivity of a cyclooctyne can be altered through (c) electronic6,3a and (d) strain modulation.7 All rateconstants are second order (M–1 s–1) and were measured at room temperature in CD3CN exceptfor values noted with an asterisk (*) which were measured in CD3OD.
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fig1: Reagent development for copper-free click chemistry. (a) The 1,3-dipolarcycloaddition between azides and cyclooctynes. (b) Oct, the firstcyclooctyne developed as a bioorthogonal reagent, and its correspondingsecond-order rate constant for the reaction with benzyl azide.5,6 The reactivity of a cyclooctyne can be altered through (c) electronic6,3a and (d) strain modulation.7 All rateconstants are second order (M–1 s–1) and were measured at room temperature in CD3CN exceptfor values noted with an asterisk (*) which were measured in CD3OD.

Mentions: Since its initial introduction as a bioorthogonalreaction, thestrain-promoted 1,3-dipolar cycloaddition between cyclooctynes andazides (Figure 1a) has been utilized in a rangeof biological studies.1 The reaction wasdeveloped in response to the dearth of tools available for the studyof biomolecules in their native environments, and was designed toproceed rapidly and selectively in vivo without perturbingnative biochemical functionality. Due to the strain activation inherentto cyclooctynes,2 the reaction proceedsat a rate that is sufficient for in vivo labelingwhile avoiding the use of the toxic copper(I) catalysts traditionallyemployed in “click chemistry” with terminal alkynes.3,4 As a result, the reaction between cyclooctynes and azides is oftenreferred to as “copper-free click chemistry.”


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)

Reagent development for copper-free click chemistry. (a) The 1,3-dipolarcycloaddition between azides and cyclooctynes. (b) Oct, the firstcyclooctyne developed as a bioorthogonal reagent, and its correspondingsecond-order rate constant for the reaction with benzyl azide.5,6 The reactivity of a cyclooctyne can be altered through (c) electronic6,3a and (d) strain modulation.7 All rateconstants are second order (M–1 s–1) and were measured at room temperature in CD3CN exceptfor values noted with an asterisk (*) which were measured in CD3OD.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Reagent development for copper-free click chemistry. (a) The 1,3-dipolarcycloaddition between azides and cyclooctynes. (b) Oct, the firstcyclooctyne developed as a bioorthogonal reagent, and its correspondingsecond-order rate constant for the reaction with benzyl azide.5,6 The reactivity of a cyclooctyne can be altered through (c) electronic6,3a and (d) strain modulation.7 All rateconstants are second order (M–1 s–1) and were measured at room temperature in CD3CN exceptfor values noted with an asterisk (*) which were measured in CD3OD.
Mentions: Since its initial introduction as a bioorthogonalreaction, thestrain-promoted 1,3-dipolar cycloaddition between cyclooctynes andazides (Figure 1a) has been utilized in a rangeof biological studies.1 The reaction wasdeveloped in response to the dearth of tools available for the studyof biomolecules in their native environments, and was designed toproceed rapidly and selectively in vivo without perturbingnative biochemical functionality. Due to the strain activation inherentto cyclooctynes,2 the reaction proceedsat a rate that is sufficient for in vivo labelingwhile avoiding the use of the toxic copper(I) catalysts traditionallyemployed in “click chemistry” with terminal alkynes.3,4 As a result, the reaction between cyclooctynes and azides is oftenreferred to as “copper-free click chemistry.”

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