Strain-promoted 1,3-dipolar cycloadditions of diazo compounds with cyclooctynes

Article abstract of DOI:10.1139/V10-112

Strain-promoted cycloadditions of diazo compounds with dibenzocyclooctyne proceed with second-order rate constants of >10 L mol^-1s ^-1 at 25 °C. These reactions display rate constants that are comparable or greater than those of the analogous reactions of nitrones or azides with cyclooctynes.

Full text of DOI:10.1139/V10-112

148
Strain-promoted 1,3-dipolar cycloadditions of
diazo compounds with cyclooctynes
Joseph Moran, Craig S. McKay, and John Paul Pezacki
Abstract: Strain-promoted cycloadditions of diazo compounds with dibenzocyclooctyne proceed with second-order rate
constants of >10 L mol–1 s–1 at 25 8C. These reactions display rate constants that are comparable or greater than those of
the analogous reactions of nitrones or azides with cyclooctynes.
Key words: metal-free click chemistry, diazo compounds, 1,3-dipolar cycloaddition, dibenzocyclooctyne, rate constants.
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Resume : Les cycloadditions catalysees par une tension de composes diazo avec le dibenzocyclooctyne se produisent avec
–1 –1
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des constantes de vitesse du deuxieme ordre superieures a 10 L mol s , a 25 8C. Les constantes de vitesse de ces reac-
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tions sont comparables ou superieures a celles de reactions analogues de nitrones ou d’azotures sur les cyclooctynes.
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Mots-cles : chimie par cliquage sans metal, composes diazo, cycloaddition 1,3-dipolaire, dibenzocyclooctyne, constantes
de vitesse.
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[Traduit par la Redaction]
Fig. 1. Overview of strain-promoted 1,3-dipolar cycloadditions of
azides, nitrones, and diazo compounds with cyclooctynes.
Introduction
‘‘Click chemistry’’ was first coined by Kolb et al. in
2001,1 and has come to describe chemical reactions that are
rapid, selective, thermodynamically favourable, and devoid
of side products.1 In less than a decade, this philosophy has
been embraced in numerous areas of the chemical sciences,
including small-molecule library synthesis,2 the construction
of supramolecular materials,3 and biomolecule conjugation.4
Although the vast majority of these examples have relied on
the copper-catalyzed [3+2] azide–alkyne cycloaddition
(CuAAC) to provide a reliable reaction, biological applica-
tions have demanded the development of ‘‘click’’ reactions
that do not require the presence of toxic copper species.
Biocompatible variants that are kinetically driven by strain-
release of cyclooctynes activated by gem difluoro5a–5c or
dibenzo5d groups have subsequently been shown to be as
effective for azide–alkyne cycloadditions without the re-
quirement of copper catalysis. Other bio-orthogonal reac-
tions involving 1,3-dipoles, such as nitrile oxides6 or
photochemically generated nitrile imines,7 have also been
reported and have reaction kinetics that are comparable or
superior to azide–alkyne cycloadditions and are also highly
chemoselective in the context of biological systems.
valuable as a means for reducing the required concentration
of labeling reagents in bioorthogonal reactions. Inspired by
the pioneering work done by Huisgen et al.10 on 1,3-dipolar
cycloadditions of diazoalkanes with acyclic alkynes,10–12 we
set out to investigate whether a strain-promoted variant
could serve as a rapid alternative to reactions of nitrones or
azides with cyclooctynes (Fig. 1).13 Herein, we report that
diazoalkanes are rapid dipoles for 1,3-dipolar cycloadditions
with cyclooctynes.
Our laboratory has recently demonstrated that strain-
promoted cycloadditions of nitrones with cyclooctynes are
up to 25 times faster than comparable reactions of azides.8
Nitrone cycloadditions have also been successfully applied
to protein functionalization.9 Increased reaction rates are
Received 28 April 2010. Accepted 30 June 2010. Published on the NRC Research Press Web site at canjchem.nrc.ca on 8 January 2011.
This article is part of a Special Issue dedicated to Professor J. C. Scaiano on the occasion of his 65th birthday.
J. Moran. Steacie Institute for Molecular Sciences, National Research Council of Canada, 100 Sussex Drive, Ottawa, ON K1A 0R6,
Canada.
C.S. McKay and J.P. Pezacki.1 Steacie Institute for Molecular Sciences, National Research Council of Canada, 100 Sussex Drive,
Ottawa, ON K1A 0R6, Canada; Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, ON K1N 6N5, Canada.
1Corresponding author (e-mail: John.Pezacki@nrc-cnrc.gc.ca).
Can. J. Chem. 89: 148–151 (2011)
doi:10.1139/V10-112
Published by NRC Research Press

Moran et al.
149
Table 1. Second-order rate constants, k2 (L mol–1 s–1), for the reactions of diazo compounds 1a–1d with 2.
action pathways, including carbene reaction pathways of 1c.
The cycloadducts arising from reactions of diazoalkanes 1b
and 1d underwent rapid tautomerization to the aromatic pyr-
azoles 3b and 3d, respectively. The primary cycloadduct
from the reaction of 1b with 2 underwent loss of the trime-
thylsilyl group under the aqueous reaction conditions yield-
ing 3c.
In general, 2 reacts with resonance-stabilized diazoalkanes
at rates comparable to acyclic nitrones bearing phenyl sub-
stituents at the a-position (Table 2, entries 1 and 2) or ben-
zyl azide (k2 = 0.062 L mol–1 s–1).8 However, more weakly
stabilized diazoalkanes, 1c and 1d, displayed faster intrinsic
kinetics for cycloaddition with 2 than either strained endocy-
clic nitrones (Table 2, entry 3)8 or nitrones equipped with
ester or amide9 groups at the a-position (Table 2, entries 4
and 5).
Lastly, a screen of various deuterated solvents was used
to evaluate the generality of the reaction as well as to deter-
mine if there was a solvent effect on the rate of cycloaddi-
tion. Fortunately, the reaction of 1a with 2 proceeded
to >95% yield in less than 4 h for all solvents employed
(Table 3). In contrast to the solvent effect observed with ni-
trones, where protic solvents were slowest,8 d4-methanol
Results and discussion
There are number of ways in which diazoalkanes can be
conveniently synthesized.14 Here, standard literature proce-
dures were used to prepare diazoalkanes just prior to use.15
The diazoalkane scope was evaluated with respect to its
electronics and conformational rigidity (Table 1). The reac-
tion of diphenyldiazomethane 1a with dibenzocyclooctyne 2
in d4-methanol yielded the substituted pyrazole 3a in >95%
yield within 96 min, corresponding to a second-order rate
constant, k2 = 0.07 L mol–1 s–1. Substitution with stronger
electron-withdrawing groups, such as ethyl 2-diazoacetate
1b, reduced the reaction rate by 13-fold, k2 = 0.0053 L
mol–1 s–1 (Table 1, entry 2), reaching >95% conversion
within 18 h.
Diazoalkanes bearing electron-donating groups or groups
less capable of resonance stabilization displayed dramatic
rate enhancements. Trimethylsilyl diazomethane (1c) reacted
rapidly with 2 and reached maximum conversion within
1 min, and phenyl diazomethane reached >95% conversion
within 1 min. We were unable to determine rate constants
for diazoalkanes 1c and 1d by 1H NMR, since reactions
were complete upon acquisition of the first data point. The
modest yield of 3c most likely resulted from competitive re-
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150
Can. J. Chem. Vol. 89, 2011
Table 2. Rate constants for the reactions of nitrones with 2.
However, the rate constants reported here suggest that even
unstabilized diazoalkanes should react rapidly and spontane-
ously with cyclooctyne 2 before significant thermolysis or
photolysis can occur under ambient conditions.
Conclusion
Strain-promoted cycloadditions of diazoalkanes with cy-
clooctynes represent an alternative rapid conjugation techni-
que for material sciences and
a valid method for
constructing functionalized pyrazoles. Rate enhancements
of >10 L mol–1 s–1 were observed for diazoalkanes contain-
ing electron-donating groups adjacent to the diazo moiety.
These rates are comparable with those of analogous reac-
tions involving endocyclic nitrones or nitrones bearing ester
or amide moieties at the a-position. Optimization of the
stability and reactivity of the diazoalkane group may lead to
diazoalkanes as reactive and useful alternatives to nitrone
and azide dipoles for use in strain-promoted cycloadditions
with cyclooctynes.
Table 3. Solvent screen for the reaction of 1a
with 2.
Supplementary data
Supplementary data for this article are available on the
journal Web site (canjchem.nrc.ca).
Acknowledgements
Entry
Solvent
Reaction time for 95%
conversion to 3a (min)
We thank Professor J. C. Scaiano for his pioneering work
in areas of photochemistry and physical organic chemistry,
which has inspired and enabled new research in diverse
fields.
1
2
3
4
C6D6
245 + 15
CD3OD
d6-DMSO
CD3CN
98
5
108 + 5
139 + 5
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