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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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Flagpole methyl substituents sterically hinder the transition state.(a) Front and side views of the transition state of the reaction of 6 with methyl azide. (b) Front and side views of the transitionstate of the reaction of 15 with methyl azide. Transitionstates were modeled using B3LYP/6-31G(d).
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fig5: Flagpole methyl substituents sterically hinder the transition state.(a) Front and side views of the transition state of the reaction of 6 with methyl azide. (b) Front and side views of the transitionstate of the reaction of 15 with methyl azide. Transitionstates were modeled using B3LYP/6-31G(d).

Mentions: Our experimental results alsoprovide insight into the effectsof sterics on cyclooctyne reactivity. We were surprised to find thatcompounds 14–16, which all containa flagpole substituent ortho to the alkyne, exhibit dramatic decreasesin their rates relative to the parent BARAC (k14 = 5.8 ± 0.3 × 10–2 M–1 s–1 in CD3CN, k15 = 1.9 ± 0.3 × 10–3 M–1 s–1 in CDCl3, and k16 = 9 ± 1 × 10–4 M–1 s–1 in CDCl3). Calculations show thatthese three compounds display corresponding increases in transitionstate distortion energies relative to analogues 6–13. This enhanced distortion is due to the close proximityof the substituent to the alkyne and its orientation directly towardthe path of the incoming azide, requiring both the azide and the alkyneto distort to a higher degree in the transition state. Figure 5 gives both a front and side view of the transitionstate of the reaction of compounds 6 and 15 with methyl azide, and it is clear that the methyl group is causingdisfavorable steric interactions. Even a relatively small fluorineatom in this position, as in compound 14, causes a significantincrease in transition state distortion energy (Figure 3c). By contrast, the transition state interaction energiesof compounds 14–16 are similar tothose of the other BARAC analogues. As a result, 14–16 have higher activation barriers than do the other analoguestested, resulting in the observed orders of magnitude decrease inreactivity.


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)

Flagpole methyl substituents sterically hinder the transition state.(a) Front and side views of the transition state of the reaction of 6 with methyl azide. (b) Front and side views of the transitionstate of the reaction of 15 with methyl azide. Transitionstates were modeled using B3LYP/6-31G(d).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: Flagpole methyl substituents sterically hinder the transition state.(a) Front and side views of the transition state of the reaction of 6 with methyl azide. (b) Front and side views of the transitionstate of the reaction of 15 with methyl azide. Transitionstates were modeled using B3LYP/6-31G(d).
Mentions: Our experimental results alsoprovide insight into the effectsof sterics on cyclooctyne reactivity. We were surprised to find thatcompounds 14–16, which all containa flagpole substituent ortho to the alkyne, exhibit dramatic decreasesin their rates relative to the parent BARAC (k14 = 5.8 ± 0.3 × 10–2 M–1 s–1 in CD3CN, k15 = 1.9 ± 0.3 × 10–3 M–1 s–1 in CDCl3, and k16 = 9 ± 1 × 10–4 M–1 s–1 in CDCl3). Calculations show thatthese three compounds display corresponding increases in transitionstate distortion energies relative to analogues 6–13. This enhanced distortion is due to the close proximityof the substituent to the alkyne and its orientation directly towardthe path of the incoming azide, requiring both the azide and the alkyneto distort to a higher degree in the transition state. Figure 5 gives both a front and side view of the transitionstate of the reaction of compounds 6 and 15 with methyl azide, and it is clear that the methyl group is causingdisfavorable steric interactions. Even a relatively small fluorineatom in this position, as in compound 14, causes a significantincrease in transition state distortion energy (Figure 3c). By contrast, the transition state interaction energiesof compounds 14–16 are similar tothose of the other BARAC analogues. As a result, 14–16 have higher activation barriers than do the other analoguestested, resulting in the observed orders of magnitude decrease inreactivity.

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