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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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Bond angles and reactivities of BARAC analogues. (a) BARAC analoguestargeted for our initial study of distortion/interaction modulation.(b) Reactivity was probed empirically by measuring the second-orderrate constant for the reaction of each analogue with benzyl azidein CD3CN at rt by 1H NMR spectroscopy. (c) Tableshows both calculated and measured (X-ray crystallography data shownin parentheses) alkyne bond angles for compounds 6–16 as well as measured second-order rate constants and activationfree energies (ΔG⧧exp) for the model reaction with benzyl azide. Also shown are calculatedinteraction (ΔE⧧i,calc) and total distortion energies (ΔE⧧d,calc = ΔE⧧d,calc, azide + ΔE⧧d,calc, alkyne) as wellas overall electronic energies of activation (ΔE⧧calc) and free energies of activation(ΔG⧧calc) forthe reaction of each analogue with methyl azide. All computationaldata provided for compounds 6–16 arefor the trans-BARAC isomer. *Free energies were calculatedfor the reaction in acetonitrile. **The second-order rate constantsshown for 15 and 16 were measured in CDCl3 due to the limited solubility of 15 in CD3CN.
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fig3: Bond angles and reactivities of BARAC analogues. (a) BARAC analoguestargeted for our initial study of distortion/interaction modulation.(b) Reactivity was probed empirically by measuring the second-orderrate constant for the reaction of each analogue with benzyl azidein CD3CN at rt by 1H NMR spectroscopy. (c) Tableshows both calculated and measured (X-ray crystallography data shownin parentheses) alkyne bond angles for compounds 6–16 as well as measured second-order rate constants and activationfree energies (ΔG⧧exp) for the model reaction with benzyl azide. Also shown are calculatedinteraction (ΔE⧧i,calc) and total distortion energies (ΔE⧧d,calc = ΔE⧧d,calc, azide + ΔE⧧d,calc, alkyne) as wellas overall electronic energies of activation (ΔE⧧calc) and free energies of activation(ΔG⧧calc) forthe reaction of each analogue with methyl azide. All computationaldata provided for compounds 6–16 arefor the trans-BARAC isomer. *Free energies were calculatedfor the reaction in acetonitrile. **The second-order rate constantsshown for 15 and 16 were measured in CDCl3 due to the limited solubility of 15 in CD3CN.

Mentions: The modular natureof BARAC’s synthesis7d renderedthis scaffold amenable to derivatization witharyl ring substituents. Previous analyses of the difluorinated cyclooctyneDIFO (3, Figure 1c) suggestedthat addition of fluorine atoms at the propargylic position enhancesreaction rates by increasing interaction energies and decreasing distortionenergies in the transition state.8b,8c We were curiousas to whether comparable interaction energy changes might be affectedthrough installation of fluorine atoms on BARAC’s aryl rings,and, alternatively, whether electron-donating methoxy groups wouldaffect reaction kinetics in an opposite manner. As well, we soughtto analyze the steric effects of flagpole methyl substituents on therate of the reaction. Accordingly, compounds 7–16 (Figure 3a) were selected as thetargets for our study. Compounds 7–10 possess a single fluorine atom variously positioned around BARAC’stwo aryl rings. Compound 11 is doubly fluorinated. Onthe other end of the spectrum, compounds 12 and 13 have single methoxy groups on the aryl rings. Compound 14 is monofluorinated at the flagpole position, potentiallygenerating steric hindrance in the transition state. Finally, compounds 15 and 16 possess methyl substituents at theflagpole position. All analogues were synthesized according to theroute published by Jewett et al.7d Detailsare provided in the Supporting Information (SI).


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)

Bond angles and reactivities of BARAC analogues. (a) BARAC analoguestargeted for our initial study of distortion/interaction modulation.(b) Reactivity was probed empirically by measuring the second-orderrate constant for the reaction of each analogue with benzyl azidein CD3CN at rt by 1H NMR spectroscopy. (c) Tableshows both calculated and measured (X-ray crystallography data shownin parentheses) alkyne bond angles for compounds 6–16 as well as measured second-order rate constants and activationfree energies (ΔG⧧exp) for the model reaction with benzyl azide. Also shown are calculatedinteraction (ΔE⧧i,calc) and total distortion energies (ΔE⧧d,calc = ΔE⧧d,calc, azide + ΔE⧧d,calc, alkyne) as wellas overall electronic energies of activation (ΔE⧧calc) and free energies of activation(ΔG⧧calc) forthe reaction of each analogue with methyl azide. All computationaldata provided for compounds 6–16 arefor the trans-BARAC isomer. *Free energies were calculatedfor the reaction in acetonitrile. **The second-order rate constantsshown for 15 and 16 were measured in CDCl3 due to the limited solubility of 15 in CD3CN.
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Related In: Results  -  Collection

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fig3: Bond angles and reactivities of BARAC analogues. (a) BARAC analoguestargeted for our initial study of distortion/interaction modulation.(b) Reactivity was probed empirically by measuring the second-orderrate constant for the reaction of each analogue with benzyl azidein CD3CN at rt by 1H NMR spectroscopy. (c) Tableshows both calculated and measured (X-ray crystallography data shownin parentheses) alkyne bond angles for compounds 6–16 as well as measured second-order rate constants and activationfree energies (ΔG⧧exp) for the model reaction with benzyl azide. Also shown are calculatedinteraction (ΔE⧧i,calc) and total distortion energies (ΔE⧧d,calc = ΔE⧧d,calc, azide + ΔE⧧d,calc, alkyne) as wellas overall electronic energies of activation (ΔE⧧calc) and free energies of activation(ΔG⧧calc) forthe reaction of each analogue with methyl azide. All computationaldata provided for compounds 6–16 arefor the trans-BARAC isomer. *Free energies were calculatedfor the reaction in acetonitrile. **The second-order rate constantsshown for 15 and 16 were measured in CDCl3 due to the limited solubility of 15 in CD3CN.
Mentions: The modular natureof BARAC’s synthesis7d renderedthis scaffold amenable to derivatization witharyl ring substituents. Previous analyses of the difluorinated cyclooctyneDIFO (3, Figure 1c) suggestedthat addition of fluorine atoms at the propargylic position enhancesreaction rates by increasing interaction energies and decreasing distortionenergies in the transition state.8b,8c We were curiousas to whether comparable interaction energy changes might be affectedthrough installation of fluorine atoms on BARAC’s aryl rings,and, alternatively, whether electron-donating methoxy groups wouldaffect reaction kinetics in an opposite manner. As well, we soughtto analyze the steric effects of flagpole methyl substituents on therate of the reaction. Accordingly, compounds 7–16 (Figure 3a) were selected as thetargets for our study. Compounds 7–10 possess a single fluorine atom variously positioned around BARAC’stwo aryl rings. Compound 11 is doubly fluorinated. Onthe other end of the spectrum, compounds 12 and 13 have single methoxy groups on the aryl rings. Compound 14 is monofluorinated at the flagpole position, potentiallygenerating steric hindrance in the transition state. Finally, compounds 15 and 16 possess methyl substituents at theflagpole position. All analogues were synthesized according to theroute published by Jewett et al.7d Detailsare provided in the Supporting Information (SI).

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