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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

Strain modulation throughrehybridization. (a) Ring strain in cyclooctynesincreases with increased unsaturation. We hypothesize that BARAC’sfused aryl rings and central lactam contribute significantly to thecompound’s ring strain. (b) X-ray crystal structures show thatthe nitrogen atom of BARAC’s central lactam is sp2.2 hybridized, whereas DIMAC’s amide nitrogen atom is sp2 hybridized. Thermal ellipsoid plots are shown at 50% probability.
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fig6: Strain modulation throughrehybridization. (a) Ring strain in cyclooctynesincreases with increased unsaturation. We hypothesize that BARAC’sfused aryl rings and central lactam contribute significantly to thecompound’s ring strain. (b) X-ray crystal structures show thatthe nitrogen atom of BARAC’s central lactam is sp2.2 hybridized, whereas DIMAC’s amide nitrogen atom is sp2 hybridized. Thermal ellipsoid plots are shown at 50% probability.

Mentions: The extreme distortion of BARAC’salkyne bond angles comparedto that of bond angles of other dibenzocyclooctynes may reflect adjustmentsof the cyclooctyne ring geometry to accommodate the lactam functionality.We speculate that BARAC’s endocyclic amide bond enhances theoverall ring strain of the compound by contributing some partial doublebond character to the position directly opposite the alkyne. Semi-empiricalcalculations by Meier et al. predict that the fully unsaturated cyclooctyne 25 (Figure 6a) would possess almost3-fold more ring strain than the parent cyclooctyne 19.2b A related dibenzocycloocteneyne (26, Figure 6a) has been synthesizedbut is not bench-stable,14 consistent withthe notion that ring strain increases with cyclooctyne unsaturation.BARAC shares structural features with compounds 25 and 26 but is relatively stable, prompting us to investigate theproperties of BARAC’s central amide bond.


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)

Strain modulation throughrehybridization. (a) Ring strain in cyclooctynesincreases with increased unsaturation. We hypothesize that BARAC’sfused aryl rings and central lactam contribute significantly to thecompound’s ring strain. (b) X-ray crystal structures show thatthe nitrogen atom of BARAC’s central lactam is sp2.2 hybridized, whereas DIMAC’s amide nitrogen atom is sp2 hybridized. Thermal ellipsoid plots are shown at 50% probability.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig6: Strain modulation throughrehybridization. (a) Ring strain in cyclooctynesincreases with increased unsaturation. We hypothesize that BARAC’sfused aryl rings and central lactam contribute significantly to thecompound’s ring strain. (b) X-ray crystal structures show thatthe nitrogen atom of BARAC’s central lactam is sp2.2 hybridized, whereas DIMAC’s amide nitrogen atom is sp2 hybridized. Thermal ellipsoid plots are shown at 50% probability.
Mentions: The extreme distortion of BARAC’salkyne bond angles comparedto that of bond angles of other dibenzocyclooctynes may reflect adjustmentsof the cyclooctyne ring geometry to accommodate the lactam functionality.We speculate that BARAC’s endocyclic amide bond enhances theoverall ring strain of the compound by contributing some partial doublebond character to the position directly opposite the alkyne. Semi-empiricalcalculations by Meier et al. predict that the fully unsaturated cyclooctyne 25 (Figure 6a) would possess almost3-fold more ring strain than the parent cyclooctyne 19.2b A related dibenzocycloocteneyne (26, Figure 6a) has been synthesizedbut is not bench-stable,14 consistent withthe notion that ring strain increases with cyclooctyne unsaturation.BARAC shares structural features with compounds 25 and 26 but is relatively stable, prompting us to investigate theproperties of BARAC’s central amide bond.

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