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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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Under Curtin-Hammettconditions, BARAC’s amide conformationinfluences reactivity and regioselectivity. (a) The reaction coordinatediagram displays calculated activation free energies for reactionof the parent BARAC compound 6 with methyl azide in acetonitrile.Also shown are the relative energies of cis-6 and trans-6 and the barrierto cis/trans interconversion. Transitionstate images show only the lowest-energy regioisomers. (b) Calculatedvalues for the interconversion and reaction of analogue 15 with methyl azide in acetonitrile. Transition state images showonly the lowest-energy regioisomers.
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fig7: Under Curtin-Hammettconditions, BARAC’s amide conformationinfluences reactivity and regioselectivity. (a) The reaction coordinatediagram displays calculated activation free energies for reactionof the parent BARAC compound 6 with methyl azide in acetonitrile.Also shown are the relative energies of cis-6 and trans-6 and the barrierto cis/trans interconversion. Transitionstate images show only the lowest-energy regioisomers. (b) Calculatedvalues for the interconversion and reaction of analogue 15 with methyl azide in acetonitrile. Transition state images showonly the lowest-energy regioisomers.

Mentions: We calculated the barrier to amide bond isomerization for BARAC(6) and analogues 15 and 16 (a and b of Figure 7). For BARAC, the barrierto cis/trans isomerization is 15.9kcal/mol. With the energy of trans-BARAC set to 0kcal/mol, reaction of the trans-conformer with methylazide has an energetic barrier of 24.0 or 24.1 kcal/mol for formationof the syn- and anti-regioisomers,respectively. Isomerization to and reaction of the cis-conformer have barriers of 27.4 (anti) and 27.6(syn) kcal/mol, respectively. Because the energeticbarrier to isomerization is significantly lower than the barrier toreaction, we hypothesize that BARAC isomerizes during the course ofthe cycloaddition. However, because the activation energy for reactionof the trans-isomer is lower than the activationenergy for isomerization to and reaction of the cis-isomer, we conclude that BARAC (6) reacts mainly throughthe trans-isomer. As a result, the energetic barriersshown in Figure 7a, which predict a roughly1:1 ratio of regioisomeric products, accurately predict the experimentallyobserved ratio of regioisomers (also 1:1).


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)

Under Curtin-Hammettconditions, BARAC’s amide conformationinfluences reactivity and regioselectivity. (a) The reaction coordinatediagram displays calculated activation free energies for reactionof the parent BARAC compound 6 with methyl azide in acetonitrile.Also shown are the relative energies of cis-6 and trans-6 and the barrierto cis/trans interconversion. Transitionstate images show only the lowest-energy regioisomers. (b) Calculatedvalues for the interconversion and reaction of analogue 15 with methyl azide in acetonitrile. Transition state images showonly the lowest-energy regioisomers.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig7: Under Curtin-Hammettconditions, BARAC’s amide conformationinfluences reactivity and regioselectivity. (a) The reaction coordinatediagram displays calculated activation free energies for reactionof the parent BARAC compound 6 with methyl azide in acetonitrile.Also shown are the relative energies of cis-6 and trans-6 and the barrierto cis/trans interconversion. Transitionstate images show only the lowest-energy regioisomers. (b) Calculatedvalues for the interconversion and reaction of analogue 15 with methyl azide in acetonitrile. Transition state images showonly the lowest-energy regioisomers.
Mentions: We calculated the barrier to amide bond isomerization for BARAC(6) and analogues 15 and 16 (a and b of Figure 7). For BARAC, the barrierto cis/trans isomerization is 15.9kcal/mol. With the energy of trans-BARAC set to 0kcal/mol, reaction of the trans-conformer with methylazide has an energetic barrier of 24.0 or 24.1 kcal/mol for formationof the syn- and anti-regioisomers,respectively. Isomerization to and reaction of the cis-conformer have barriers of 27.4 (anti) and 27.6(syn) kcal/mol, respectively. Because the energeticbarrier to isomerization is significantly lower than the barrier toreaction, we hypothesize that BARAC isomerizes during the course ofthe cycloaddition. However, because the activation energy for reactionof the trans-isomer is lower than the activationenergy for isomerization to and reaction of the cis-isomer, we conclude that BARAC (6) reacts mainly throughthe trans-isomer. As a result, the energetic barriersshown in Figure 7a, which predict a roughly1:1 ratio of regioisomeric products, accurately predict the experimentallyobserved ratio of regioisomers (also 1:1).

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