Experimental investigation on the mechanism of chelation-assisted, copper(II) acetate-accelerated azide-alkyne cycloaddition

Article abstract of DOI:10.1021/ja203733q

A mechanistic model is formulated to account for the high reactivity of chelating azides (organic azides capable of chelation-assisted metal coordination at the alkylated azido nitrogen position) and copper(II) acetate (Cu(OAc)₂) in copper(II)-

Full text of DOI:10.1021/ja203733q

ARTICLE
pubs.acs.org/JACS
Experimental Investigation on the Mechanism of Chelation-Assisted,
Copper(II) Acetate-Accelerated AzideꢀAlkyne Cycloaddition
Gui-Chao Kuang, Pampa M. Guha, Wendy S. Brotherton, J. Tyler Simmons, Lisa A. Stankee,
Brian T. Nguyen, Ronald J. Clark, and Lei Zhu*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306-4390, United States
S Supporting Information
b
ABSTRACT: A mechanistic model is formulated to account for
the high reactivity of chelating azides (organic azides capable of
chelation-assisted metal coordination at the alkylated azido
nitrogen position) and copper(II) acetate (Cu(OAc)2) in
copper(II)-mediated azideꢀalkyne cycloaddition (AAC) reac-
1
tions. Fluorescence and H NMR assays are developed for
monitoring the reaction progress in two different solvents,
methanol and acetonitrile. Solvent kinetic isotopic effect and
premixing experiments give credence to the proposed different
induction reactions for converting copper(II) to catalytic
copper(I) species in methanol (methanol oxidation) and acet-
onitrile (alkyne oxidative homocoupling), respectively. The
kinetic orders of individual components in a chelation-assisted,
copper(II)-accelerated AAC reaction are determined in both methanol and acetonitrile. Key conclusions resulting from the kinetic
studies include (1) the interaction between copper ion (either in +1 or +2 oxidation state) and a chelating azide occurs in a fast, pre-
equilibrium step prior to the formation of the in-cycle copper(I)-acetylide, (2) alkyne deprotonation is involved in several kinetically
significant steps, and (3) consistent with prior experimental and computational results by other groups, two copper centers are
involved in the catalysis. The X-ray crystal structures of chelating azides with Cu(OAc)2 suggest a mechanistic synergy between
alkyne oxidative homocoupling and copper(II)-accelerated AAC reactions, in which both a bimetallic catalytic pathway and a base
are involved. The different roles of the two copper centers (a Lewis acid to enhance the electrophilicity of the azido group and a two-
electron reducing agent in oxidative metallacycle formation, respectively) in the proposed catalytic cycle suggest that a mixed
valency (+2 and +1) dinuclear copper species be a highly efficient catalyst. This proposition is supported by the higher activity of the
partially reduced Cu(OAc)2 in mediating a 2-picolylazide-involved AAC reaction than the fully reduced Cu(OAc)2. Finally, the
discontinuous kinetic behavior that has been observed by us and others in copper(I/II)-mediated AAC reactions is explained by the
likely catalyst disintegration during the course of a relatively slow reaction. Complementing the prior mechanistic conclusions drawn
by other investigators, which primarily focus on the copper(I)/alkyne interactions, we emphasize the kinetic significance of
copper(I/II)/azide interaction. This work not only provides a mechanism accounting for the fast Cu(OAc)2-mediated AAC
reactions involving chelating azides, which has apparent practical implications, but suggests the significance of mixed-valency
dinuclear copper species in catalytic reactions where two copper centers carry different functions.
’ INTRODUCTION
which the azide and alkyne substrates can be channeled via various
pathways to 1,4-substituted-1,2,3-triazoles over the potential en-
ergy surface despite the tremendous variations in substrate struc-
tures and reaction conditions. Such a situation renders mechanistic
investigations challenging, because the sequence of the events on
the reaction coordinate and the structures of the intermediates and
catalytic species vary when the reaction parameters are altered as
needed in kinetic investigations.
The discovery of copper(I)-catalyzed azideꢀalkyne cycloaddi-
tion (CuAAC) reaction by Fokin/Sharpless1 and Meldal2 groups
has stimulated advances acrossmanyscientific disciplines.3ꢀ6 Itisa
simple yet powerful tool to put molecular pieces together, for
instance, in applications of bioconjugation,7 surface modification,8
and syntheses of new polymeric materials.9 One of the most
astonishing facts of the CuAAC reaction is that it proceeds under
a large number of conditions that are developed,5 not necessarily
to make the reaction itself faster, but to accommodate various
stringent requirements rarely faced in a laboratory of traditional
synthetic organic chemistry.10,11 The ability of the CuAAC
reaction to proceed under a vast array of different conditions
suggests that a high degree of mechanistic redundancy exist, by
Two significant characteristics in the prevailing mechanistic
model of the CuAAC reaction12ꢀ16 are the requirements of
a terminal alkyne substrate and a copper catalyst in the +1
Received: May 2, 2011
Published: August 01, 2011
r
2011 American Chemical Society
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oxidation state. There are two ramifications of these two observa-
tions that are relevant to this Article: first, the recognition of the
roles of terminal alkyne and copper(I) understandably led to the
accepted mechanistic significance of copper(I)ꢀacetylide.16 The
importance of copper(I/II)ꢀazide interaction, on the other hand,
has been relatively understated.17 Second, anecdotal reports did
appear where copper(II) salts apparently “catalyze” the CuAAC
reactions.18ꢀ24 These earlier observations were suspected at
times as arising from using a copper(II) salt that was contami-
nated with a small amount but potent copper(I) catalytic
species.5 Consequently, the likelihood of the active engagement
of copper(II) in CuAAC reactions was largely dismissed.5,25 In
this Article, we describe the mechanistic significance of copper(I/
II)ꢀazide interaction and the possible beneficial effect of a direct
participation of copper(II) in CuAAC reactions.
Mizuno et al. reported that a dicopper(II)-substituted silico-
tungstate accelerates the CuAAC reaction.26 A preceding alkyne
oxidative homocoupling (OHC) reaction was postulated to
generate the needed copper(I) catalyst for the subsequent
CuAAC reaction. Gratifyingly, a kinetic study was conducted
to support the hypothesis of the copper(I)-generating induction
process,26 which provides an appropriate foundation for the
discussion of the findings reported herein.
Figure 1. A mechanistic proposal by Fokin et al.1,16 L: A ligand or a
counterion associated with copper(I/II). i.p.: Induction period. r.d.s.:
Rate-determining step. The numbering of azide and acetylide is marked
in blue. The brackets around “CuLn” indicate that bi- or polynuclear
copper(I) species may be involved.
unveiled in the mechanistic studies, which have profound effects
on the efficiency of the reaction.16
Our group showed that organic azides that are capable of
chelating copper(II) at the alkylated azido nitrogen (chelating
azides) have high reactivity in CuAAC reactions in the presence of
an air-stable copper(II) salt without the addition of a reducing
agent as usually required for in situ copper(I) generation.27 In the
current work, we present kinetic and structural data to map out a
mechanistic pathway of this variant of the CuAAC reaction. The
discussion of our mechanistic investigation is conducted under the
context of the currently known mechanistic models.12ꢀ15,26 The
newly discovered featuresinourmodel emphasize the dependence
of mechanism on substrate structures (e.g., chelating azide vs
nonchelating azide) and counterion of the copper(II) salt. In
addition toadvancingthe understanding inthe multifacetednature
of the mechanisms of CuAAC reactions,16 this work may offer
insights into other copper(I/II)-involved catalytic processes.
Before delving into our findings, a summary of the current
mechanistic understanding of the CuAAC reaction is warranted.
As illustrated in the simplified model in Figure 1, the in-cycle
copper(I) catalyst may be generated in an induction period (i.p.,
step A) by reducing an air-stable copper(II) salt. The formation of
the copper(I) acetylide (step B) follows, which binds the azide
(step C) to set up an intramolecular nucleophilic attack step. The
rate-determining ring closure (step D), as supported by computa-
tional studies,12,15 involves the oxidation of copper(I) to copper-
(III) upon the formation of a six-membered (or larger if multiple
copper centers are involved28) metallacycle.29,30 The metallacycle
readily converts to copper(I) triazolide (step E),31 which exits the
catalytic cycle upon protonation (step F). The protonation step
has been suggested to be kinetically significant when the overall
proton donating ability of the reaction mixture is low (e.g., when
an aprotic solvent is used).31 Therefore, it is likely that more than
one elementary step in the catalytic cycle may affect the overall rate
of the reaction. The formations of copper(I) acetylide32,33 and
copper(I) triazolide31 have been directly observed during CuAAC
reactions. Many other lines of experimental and computational
evidence are consistent with this model.16 The formation and
retention of unaggregated copper(I) species, the accessibility of
the copper(I) acetylide by an azide, and the involvement of two
copper centers in the rate-determining step34 are the subtle issues
Our group recently found that Cu(OAc)2 in alcoholic solvents
mediates the CuAAC reaction without the deliberate addition of a
reducing agent.27,35 On the basis of the mechanistic model in
Figure 1, the catalytic copper(I) species was postulated to emerge
in an induction period via alcohol oxidation and/or alkyne oxidative
homocoupling (OHC) reaction.27 This hypothesis is consistent
with experimental observations of other groups.26,36 In particular,
the OHC-enabled copper(I) generation in a dicopper(II)-substi-
tuted silicotungstate-accelerated CuAAC process has been invoked
by Mizuno et al. and substantiated by their kinetic studies.26
The key motivations that propelled us to conduct the mechanistic
investigation of the Cu(OAc)2-accelerated CuAAC reaction are the
following two observations. First, chelating azides, such as com-
pounds 1ꢀ6, are superior substrates under the Cu(OAc)2-acceler-
ated conditions.27,35,37 Second, Cu(OAc)2 is the most effective
copper(II) salt that drives the CuAAC reaction in nonoxidizable
solvents (see next section) in which other counterions are largely
ineffective. Herein, we reveal how chelating azides and Cu(OAc)2
change the potential energy landscape of the CuAAC reaction.
’ RESULTS AND DISCUSSION
This section is organized as the following: first, various
solvents, alkynes, and counterions are screened for their effects
on the efficiency of CuAAC reactions involving a chelating azide
as represented by the time required for a complete conversion.
The appropriate conditions are subsequently selected for kinetic
1
experiments using fluorescence and H NMR assays to gain
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Table 1. Solvent Effect on the Cu(OAc)2-Accelerated
addition of a copper(I) catalyst. The shorter time frames required
for full conversions in alcoholic solvents than that in aprotic
organic solvents are consistent and striking. Three factors might
contribute to the “faster” reactions in alcoholic solvents: (1) the
induction period required for copper(I) generation in an aprotic
solvent, presumably via the OHC reaction, may be relatively
long, whereas in most alcoholic solvents, alcohol oxidation
provides an additional pathway to copper(I). (2) The proton-
ation of copper(I)ꢀtriazolide, which may affect the overall
rate,17,31 is rapid in an alcoholic solvent. In an aprotic solvent,
however, the only proton sources are the terminal alkyne, the
protonated azide 1 or 2 (resulting from deprotonation of alkyne),
and the minimal amount of water introduced with Cu(OAc)2.
Therefore, the protonation step may be relatively slow due to the
paucity of proton donors.40 (3) The dynamic exchange between
the counterion and azide or alkyne substrate to the catalytic
copper centers, which has been emphasized as important in
CuAAC reactions,17,41 may be faster in a protic solvent than that
in an aprotic solvent.
The reactions proceed well under the aqueous conditions
(entry 8). Once again, similar color transitions from blue/green
to yellow was observed (Figure S3). The reactions are reasonably
rapid, much faster than the CuAAC reactions under similar
conditions reported by Reddy et al. (a 20 h reaction time was
reported).18 The difference reflects the high reactivity of the
chelating azides 1. The relatively inefficient reaction involving
azide 2 under the conditions of entry 8 may be attributed to the
protonation of the tertiary amino group at neutral pH, which
hampers the chelation between 2 and the copper centers. The
effectiveness of Cu(OAc)2 in enabling rapid CuAAC reactions
involving chelating azides offers promises in developing CuAAC-
based bioconjugation protocols without the sensitivity to molec-
ular oxygen.
On the basis of the solvent screening data, CH3OH and
CH3CN were chosen as representative solvents for kinetic studies.
In either solvent, all species involved in the reactions have
satisfactory solubilities, which allow spectroscopic interrogation
without complication due to aggregation. In addition, the
induction processes during which copper(I) catalytic species is
generated are expected to differ in these two solvents: alcohol
oxidation in CH3OH and OHC reaction in CH3CN. It should be
noted that copper(II) is a stronger oxidant in CH3CN than in
most other solvents.42 Therefore, a solvent environment of
CH3CN provides a thermodynamic driving force for copper(II)
reduction.
2. Alkyne Screening. The reactivities of various alkynes
against azide 1ꢀ3 were studied in CH3OH (Table 2) and CH3CN
(Table S1), respectively. In either solvent, no apparent correla-
tion between the structure of alkyne and the efficiency of the
reaction under the preparative, heterogeneous conditions was
observed, although under homogeneous reaction conditions
where the kinetic experiments are conducted it was revealed
otherwise (see section 8). One exception is 3,3-dimethylbutyne
(entry 7) whose slow reactions can be attributed to the steric
effect imposed by the t-butyl group. The pyridyl-containing azide
1 consistently takes a shorter time to finish the reaction than the
tertiary amino-containing 2 and carboxylate-containing 3, parti-
cularly in CH3CN (see Table S1). In reactions involving 2 and 3,
a very rapid reaction was routinely observed via TLC during the
early phase of the reaction (5ꢀ30 min). However, the reaction
slows subsequently to result in an overall less efficient reaction
than that involving 1. The two-phase observation may be caused
CuAAC Reactionsa
entry
solvent
timeb (T1)
timeb (T2)
1
2
3
4
5
6
7
8
CH2Cl2
CH3CN
THF
1 h
55 min
5 h
2.8 h
3.5 h
3.5 h
toluene
tBuOH
CH3OH
iPrOH
3 h
8 h (58%)c
<5 min
<5 min
<5 min
<5 min
<5 min
<5 min
<5 min
2 h (89%)c
water ([HEPES] = 0.5 M, pH 7.0)
a Reaction conditions: azide 1 or 2 (0.2 mmol), phenylacetylene (0.22
mmol), Cu(OAc)2 H2O (5 mol %), solvent (0.5 mL), room tempera-
3
ture. b Time for the azide to disappear on TLC, followed by the
1
confirmation of a full conversion (>95%) by H NMR. c Incomplete
conversion with percentage yield in parentheses.
mechanistic pictures in two different concentration regimes.38
Following the kinetic studies, preliminary mechanistic models
are proposed that account for the reaction orders of individual
components. The structural studies focus on the interactions
between Cu(OAc)2 and chelating azide or terminal alkyne, based
on which the final mechanistic model is described to present our
proposition on the unique role of Cu(OAc)2 in the CuAAC
reactions.
1. Solvent Screening. The reactions between azides 1 or 2
and phenylacetylene were selected for screening for solvent
effects. The solvents listed in Table 1 are arranged into two
groups. The first group includes aprotic organic solvents CH2Cl2,
CH3CN, THF, and toluene (Table 1, entries 1ꢀ4). The hetero-
geneous reaction mixture shows green-blue color throughout the
reaction in most cases, while the colors of the others change to yellow
(e.g., see Figure S1). The fading of the bluish color of the reaction
mixture over the course of the reaction is an indication that the
copper(II) precatalyst is transformed into copper(I) catalyst-
(s).26,27 The reactions generally complete within 1ꢀ5 h. In some
cases, an initial rapid conversion is followed by a much slower
phase to reach completion. Such a discontinuous kinetic profile is
indicative of the inactivation of the catalyst over the course of the
reaction.17,39
Protic solvents (Table 1, entries 5ꢀ8) constitute the second
group. In alcoholic solvents (entries 5ꢀ7), the reaction mixture
is more homogeneous than those in the first group of aprotic
solvents. Sharp color transitions from blue/greenish to yellow are
observed in most cases (Figure S2). The reactions reach com-
pletion in 5 min or less without any apparent difference in
reactivity between azides 1 and 2. These are some of the fastest
solution-phase CuAAC reactions reported, yet without the direct
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Table 2. Effect of Alkyne on the Cu(OAc)2-Accelerated Reactions Involving Chelating Azides 1ꢀ3a
a Reaction conditions: azide (0.2 mmol), alkyne (0.22 mmol), Cu(OAc)2 (5 mol %), in CH3OH (0.5 mL), room temperature. For reactions involving
azide 3, TEA (0.2 mmol) was included. b Time for azide to disappear on TLC, followed by the confirmation of a full conversion (>95%) by 1H NMR.
c Incomplete conversion with percentage yield in parentheses.
Table 3. Effect of Counterion on the Copper(II)-Accelerated Reactions Involving Azide 4a
entry
CuII salt
time (conversion)b (CH3CN)
time (conversion)b (CH3OH)
time (conversion)b (tBuOH/NaAsc)c
1
2
3
4
5
6
7
Cu(OAc)2
CuCl2
25 min (>95%)
16 h (14%)
1 h (>95%)
1 h (60%)
1 h (27%)
1 h (14%)
1 h (14%)
1 h (40%)
1 h (26%)
<5 min (>95%)
50 min (>95%)
<5 min (>95%)
<5 min (>95%)
60 min (>95%)
45 min (>95%)
30 min (>95%)
CuSO4
16 h (33%)
Cu(NO3)2
Cu(ClO4)2
Cu(OTf)2
Cu(CF3CO2)2
18 h (27%)
16 h (8%)
14 h (86%); 1 h (10%)
16 h (89%); 1 h (2%)
a Reaction conditions: 2-azidomethylquinoline 4 (0.2 mmol), phenylacetylene (0.22 mmol), copper(II) salt (5 mol %), room temperature. The 1H
NMR of the triazole product is consistent with the reported data in ref 27. b The conversion values in parentheses were determined by 1H NMR. c NaAsc:
sodium ascorbate.
by the reorganization of the catalyst structure during the course
of the reaction, which alters, and often lowers, the catalytic
activities (see section 11).39 The transformation of Cu(OAc)2
structure in the presence of 3-azidopropionate 3 is evident in the
crystal structure shown in Figure 15C. Because of such complica-
tions involving azides 2 and 3, azide 1 was used in the majority of
the kinetic experiments described herein.
an example of chelating azides,43 and phenylacetylene (Table 3).
In the nonoxidizable solvent CH3CN, acetate stands out as the
only viable counterion that affords a rapid conversion (within an
hour). All other counterions tested are far inferior. The coordi-
nating strength of a counterion (e.g., strongly coordinating
chloride vs noncoordinating perchlorate or triflate) does not
appear to be a significant factor. The reactivity difference
between Cu(OAc)2 and Cu(CF3CO2)2 will be addressed in
section 10.2, ref 78. When an oxidizable solvent is used (e.g.,
3. Counterion Screening. The effect of counterion was eval-
uated using the reaction between 2-azidomethylquinoline 4, as
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Scheme 1a
a (a) 5 mol % Cu(OAc)2 H2O, CH3OH, or CD3CN. The fluorescence quantum yields (ϕ) were measured in CH3OH.
3
Figure 2. (A) Fluorescence spectral changes (λex 320 nm) during the fluorogenic CuAAC reaction between alkyne 7 and azide 1. Reaction conditions: 7
(10 μM), 1 (5 mM), Cu(OAc)2 H2O (10 μM) in CH3OH. (B) 1H NMR spectral evolution during the CuAAC reaction between 7 and 1. Conditions: 7
3
(10 mM), 1 (10 mM), Cu(OAc)2 H2O (1 mM) in CD3CN.
3
CH3OH, middle column in Table 3), or other means of copper-
(II) reduction is provided (e.g., via treating with sodium ascor-
bate, right column in Table 3), the dependence of reaction
efficiency on counterion diminishes. These observations suggest
the requirement of acetate in generating the catalytic copper(I)
species in a nonoxidizable solvent during the induction period,
presumably involving the OHC process.
of Cu(OAc)2 up to 15 μM, the fluorescence of the triazole
product 8 (15 μM) is unaffected (Figure S4). In addition, the
formation of fluorescent diyne side product 9 (Scheme 1) is
negligible in CH3OH (Figure S5). Therefore, the observed
fluorescence enhancement (e.g., in Figure 2A) can be correlated
to the formation of fluorescent triazole product 8.
The reaction (Scheme 1) in CH3CN requires millimolar
concentration of alkyne 7 to proceed within a reasonable time
frame.47 However, the linearity between fluorescence intensity
and [8] no longer applies in this concentration regime.46
Furthermore, the fluorescence of the diyne side product 9
produced in CH3CN is difficult, if not impossible, to be separated
from that of the triazole product 8. Therefore, the reaction in
CD3CN (solvent deuteration does not affect the reaction
progress) was analyzed using 1H NMR.
1
4. Fluorescence and H NMR Assays. In a previous kinetic
study conducted by Finn, Fokin et al.,13 aliquots of the reaction
mixture were taken and quenched before subjecting to LCꢀMS
analysis. We aimed to develop an operationally simple kinetic
assay that allows real-time monitoring of the reaction.44 Fahrni
et al. reported that an analogue of alkyne 7 (Scheme 1) under-
goes fluorescence enhancement upon forming the triazole pro-
duct with an organic azide.11,45 Upon transforming 7 to triazole
8, the fluorescence quantum yield is indeed increased by 10-fold
in CH3OH (Scheme 1). Therefore, the reaction in CH3OH
shown in Scheme 1 was monitored by the growth of fluorescence
intensity at 400 nm.
As shown in Figure 2B, a clean transition from alkyne 7 to
1
triazole 8 could be monitored by H NMR spectroscopy. No
buildup of intermediates could be detected in the experiment.
The presence of a catalytic amount of Cu(OAc)2 slightly blurs
the signals of the pyridyl portions of 1 and 8 due to the
paramagnetic nature of a copper(II) salt (see the difference
between the first and second spectra from the bottom of
Figure 2B) in otherwise well-resolved NMR spectra. The product
formation was quantified via integration of the CH2 signal of
triazole 8 at 5.7 ppm or the C5ꢀH triazole hydrogen at 8.3 ppm.
5. The Induction Period. The reaction in Scheme 1 was
monitored by fluorescence at 400 nm immediately after mixing
In the fluorescence assay in CH3OH (Figure 2A), the alkyne
concentration ([7]) was in most cases kept under 10 μM so that
the fluorescence intensity could be approximated to have a linear
relationship with the triazole product concentration ([8]).46
Azide 1 was used in large excess (0.5ꢀ3.5 mM) to manage
reasonable reaction rates. The concentration of Cu(OAc)2 was
varied within 0.8ꢀ2.5 μM during its reaction order determina-
tion, which is catalytic with respect to the azide and alkyne
components. A control experiment showed that in the presence
2-picolylazide (1), alkyne 7, and Cu(OAc)2 H2O in CH3OH. In
3
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Figure 3. (A) Growth of fluorescence intensity at 400 nm of the mixture of 1 (1 mM), 7 (10 μM), and Cu(OAc)2 (10 μM) in CH3OH over time with
(red) or without (blue) premixing azide 1 and Cu(OAc)2 for 2 h. (B) Product (8) generation over time monitored by 1H NMR with (red) or without
(blue) premixing azide 1 and Cu(OAc)2. Conditions: [1] = 10 mM, [7] = 10 mM, [Cu(OAc)2] = 1 mM in CD3CN.
In CD3CN, on the contrary, premixing 2-picolylazide 1 and
Cu(OAc)2 has little effect on the induction period (Figure 3B).
We postulate that the alkyne OHC reaction provides the
required copper(I) species in CD3CN, which would not take
place until the entrance of alkyne into the reaction mixture. The
high reactivity of 2-picolylazide 1 under Cu(OAc)2-involved
conditions can be attributed, in part, to its acceleration of the
initial OHC induction reaction.
On the basis of the absorption spectral difference between
diyne 9 and alkyne 7 (Figure 5A), the generation of diyne 9 in
an OHC reaction can be monitored at 374 nm. In a control
experiment, the effect of pyridine as an additive on the efficiency
of the Cu(OAc)2-mediated OHC reaction was investigated.49
The diyne (9) formation is very slow in the absence of pyridine as
shown by the absorption at 374 nm (Figure 5B, cornflower
Figure 4. (A) Growth of fluorescence intensity at 400 nm of the mixture
trace). The addition of pyridine accelerates the reaction
of 1 (10 mM), 7 (10 μM), and Cu(OAc)2 H2O (10 μM) in CH3OH
3
(Figure 5B, garnet trace). Pyridine, however, cannot initiate
the OHC reaction using CuCl2 (resulting in unidentified
aggregates) or CuSO4 (Figure 5B, lime trace), suggesting a
productive combination of Cu(OAc)2 and pyridine in the
OHC reaction in CH3CN. 2-Picolylazide 1 may have an analo-
gous effect as pyridine, thus offering an explanation on the rapid
generation of copper(I) catalytic species via an accelerated OHC
induction reaction.50 Little absorption change at 374 nm was
observed, however, during the CuAAC reaction in CH3OH
under the conditions shown in the caption of Figure 2A
(Figure S5), suggesting that the OHC reaction is at best
marginal.
(cornflower [), CH3OD (garnet 9), and CD3OD (lime 2),
respectively.
most cases, an induction period precedes the triazole product
formation (e.g., blue trace in Figure 3A). The length of the
induction period is inversely correlated to the concentration of
azide 1 ([1]). When [1] is 3.5 mM, the induction period is barely
noticeable (Figure 7A in section 6). We hypothesize that copper-
(I) catalytic species is generated during the induction period via
the reduction of Cu(OAc)2 by CH3OH. The reduction process
appears to be aided by the presence of 2-picolylazide 1 as a base in
the oxidation of CH3OH.48 Consistent with a 2-picolylazide-
dependent copper(II) reduction process, by premixing 2-pico-
lylazide 1 and Cu(OAc)2 up to 2 h, the induction period was no
longer observed in CH3OH (see the red trace in Figure 3A).
The occurrence of methanol oxidation during the induction
period is supported by the solvent kinetic isotope effect experi-
ment when the reaction was run in CH3OH, CH3OD, or
CD3OD (Figure 4). The deuterium substitution on the methyl
group in methanol slows the reaction, whereas the deuteration of
the hydroxyl group only does not significantly alter the reaction
rate. The solvent kinetic isotope effect is consistent with the
hypothesis that in the induction reaction methanol is oxidized to
formaldehyde during which the CꢀH/D bond cleavage takes
place in the rate-determining step.
6. Reaction Orders in CH3OH. The product formation was
monitored as the fluorescence enhancement at 400 nm im-
mediately after mixing the fluorogenic alkyne 7, 2-picolylazide
1, and Cu(OAc)2 H2O. The reaction orders (Table 4, entries
3
1ꢀ3) of the three components, alkyne 7, 2-picolylazide 1, and
Cu(OAc)2 H2O, were determined under initial kinetics con-
3
ditions (Figures 6ꢀ8).51 The time course data were processed
on the basis of the method reported by Vallee et al. (see
derivations in the Supporting Information).52 Alkyne 7 shows
a first-order behavior (Figure 6). 2-Picolylazide 1, in excess
amounts, has fractional order (0.4), which suggests saturation
kinetics (Figure 7).53 The reaction is second-order in Cu-
(OAc)2 when it is maintained at catalytic levels (<5 mol %,
Figure 8). A second-order dependence on Cu(OAc)2 is
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Figure 5. (A) Absorption spectra of alkyne 7 (cornflower), triazole 8 (garnet), and diyne 9 (lime) in CH3CN at 2 μM each. (B) The growth of
absorption at 374 nm in CH3CN of the mixture of 7 (10 mM) and Cu(OAc)2 H2O (1 mM) in the presence (garnet) and absence (cornflower)
3
of pyridine, and of the mixture of 7 (10 mM) and CuSO4 5H2O (1 mM) in the presence of pyridine (lime), respectively. The absorbance values at
time = 0 are zeroed.
3
Table 4. Kinetic Orders in Various Components of CuAAC Reactions under Different Conditions
entry
component
alkyne
azide
Cu(OAc)2
solvent
order
1 (FL)a
2 (FL)
alkyne 7
1ꢀ10 μM
10 μM
5 mM
10 μM
CH3OH
CH3OH
CH3OH
CD3CN
CD3CN
CD3CN
CD3CN
CD3CN
CD3CN
0.9
0.4
azide 1
0.5ꢀ3.5 mM
5 mM
10 μM
3 (FL)
Cu(OAc)2
alkyne 7
50 μM
0.8ꢀ2.5 μM
1 mM
2.2
4 (NMR)b
5 (NMR)
6 (NMR)
7 (NMR)
8 (NMR)
9 (NMR)
3ꢀ10 mM
10 mM
10 mM
2.5
azide 1
1ꢀ10 mM
25 mM
1 mM
0.072
2.1
Cu(OAc)2
1-ethynyl-4-nitrobenzene
azide 2
25 mM
0.05ꢀ0.12 mM
1 mM
4ꢀ12 mM
10 mM
20 mM
2.3
10ꢀ20 mM
20 mM
1 mM
ꢀ0.13
1.7
Cu(OAc)2
20 mM
0.05ꢀ0.12 mM
a FL: Kinetic orders were determined in a fluorescence assay. b NMR: Kinetic orders were determined in a 1H NMR assay.
Figure 6. (A) The dependence of fluorescence time course (λex 320 nm, λem 400 nm) on [7]. Conditions: [1] = 5 mM, [Cu(OAc)2 H2O] =
3
10 μM, and [7] = 1ꢀ10 μM in CH3OH at 25 °C. (B) Plot of ln Vint versus ln[7]. The slope yields the kinetic order of 7. Vint: Initial observed rate =
d[8]/dt (M sꢀ1). The spectra taken after 48 h, assuming full conversion, are included in Figure S6.
consistent with the currently accepted kinetic model, which
favors the participation of two copper(I) centers in the metalla-
cycle formation step based on both kinetic data13 and
computation.14,15 The reaction orders of CuAAC reactions
determined by Finn, Fokin, et al.14 and Mizuno et al.27 are
included in Table S2 for comparison.
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Figure 7. (A) The dependence of fluorescence time course (λex 320 nm, λem 400 nm) on [1]. Conditions: [7] = 10 μM, [Cu(OAc)2 H2O] = 10 μM,
3
and [1] = 0.5ꢀ3.5 mM in CH3OH. (B) Plot of ln Vint versus ln[1]. The slope yields the kinetic order of 2-picolylazide 1. Vint: Initial observed rate =
d[8]/dt (M sꢀ1).
Figure 8. (A) The dependence of fluorescence time course (λex 320 nm, λem 400 nm) on [Cu(OAc)2 H2O]. Conditions: [7] = 50 μM,
3
[Cu(OAc)2 H2O] = 0.8ꢀ2.5 μM, and [1] = 5 mM in CH3OH. (B) Plot of ln Vint versus ln[Cu(OAc)2 H2O]. The slope yields the kinetic order
3
3
of Cu(OAc)2 H2O. Vint: Initial observed rate = d[8]/dt (M sꢀ1).
3
7. Reaction Orders in CD3CN.54 The Cu(OAc)2-accelerated
CuAAC reaction between alkyne 7 and 2-picolylazide 1 proceeds
smoothly in CD3CN (Figure 2B). The kinetic orders of various
components were determined via integrating the 1H NMR signals,
which are sharp enough in the presence of up to 10 mol %
progressively longer induction period (Figure 10A). The ob-
served zero order in 2-picolylazide 1 (Figure 10B) supports a pre-
equilibrium process in which the copper(II) center is saturated
by 1 prior to its reduction to copper(I) and the entry to the
catalytic cycle. The faster interaction of 2-picolylazide 1 with
copper(II) than that of alkyne 7 is also evident from the 1H NMR
spectra of the initial mixture (Figure 2B), where the signal of
azide 1 is significantly blurred due to copper(II) binding during
the first 20 min of the reaction. The peaks of alkyne 7 are barely
affected.
Cu(OAc)2 H2O. Invariably, an induction period was observed
3
(e.g., in Figure 9A). The slope of the immediate linear portion
following the induction period, which is defined as the “reaction
phase”, is considered as the initial rate of each reaction. The kinetic
order of alkyne 7 is 2.5 (Figure 9B), as opposed to 0.9 in CH3OH.
Three possibilities may account for a kinetic order of or over two:
(1) two alkyne molecules take part in the rate-determining step,
(2) two or more alkyne molecules are involved in separate
kinetically significant steps, and (3) an autoinductive process55 is
operating. The last possibility is not consistent with the observa-
tion that addition of the triazole product 8 barely affects the
reaction (Figure S9). The mechanistic model that we propose in
section 9 is consistent with the second scenario.
The second order in Cu(OAc)2 H2O at a true catalytic,
3
less than 0.5% loading level (Figure 11) is in agreement with
that reported by Fokin and Finn under the typical copper(I)-
catalyzed conditions.13 Two copper ions acting in concert
are considered to best activate alkyne and/or azide toward
the formation of the key CꢀN bond in the metallacycle
intermediate.
As shown in Figures 9 and 10, the length of the induction
period is dependent on the concentrations of both azide 1 and
alkyne 7, suggesting the participation of these two components
When the concentration of 2-picolylazide ([1]) is lowered, the
rate of the reaction phase is largely unchanged following a
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Figure 9. (A) The dependence of reaction time course on [7]. Conditions: [1] = 10 mM, [Cu(OAc)2 H2O] = 1 mM, and [7] = 3ꢀ10 mM in CD3CN
3
at 25 °C. Full conversions of each reaction would afford 8 at 3, 4, 6, 8, and 10 mM, respectively. (B) Plot of ln Vint versus ln[7]. The slope yields the kinetic
order of 7. Vint: Initial observed rate = d[8]/dt (M sꢀ1).
Figure 10. (A) The dependence of reaction time course on [1]. Conditions: [1] = 4ꢀ15 mM, [Cu(OAc)2 H2O] = 1 mM, and [7] = 10 mM in CD3CN
3
at 25 °C. Full conversions of each reaction would afford 8 at 4, 6, 8, 10, and 10 mM, respectively. (B) Plot of ln Vint versus ln[1]. The slope yields the
kinetic order of 1. Vint: Initial observed rate = d[8]/dt (M sꢀ1).
Figure 11. (A) The dependence of reaction time course on [Cu(OAc)2 H2O]. Conditions: [1] = 25 mM, [Cu(OAc)2 H2O] = 0.05ꢀ0.12 mM, and
3
3
[7] = 25 mM in CD3CN at 25 °C. Full conversions of each reaction would afford 8 at 25 mM. (B) Plot of ln Vint versus ln[Cu(OAc)2 H2O]. The slope
3
yields the kinetic order of Cu(OAc)2 H2O. Vint: Initial observed rate = d[8]/dt (M sꢀ1).
3
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Scheme 2a
a Conditions: (a) 5 mol % Cu(OAc)2 H2O, CD3CN.
3
Scheme 3a
a Conditions: (a) 5 mol % Cu(OAc)2 H2O, CD3CN. R = ꢀNO2, ꢀF, ꢀH, ꢀOCH3, and ꢀN(CH3)2.
3
Figure 12. The time courses of triazole product formation determined by integrating 1H NMR signals. Conditions: [1] = 20 mM, [alkyne] = 20 mM,
and [Cu(OAc)2 H2O] = 1 mM in CD3CN at 40 °C. (A) Phenylacetylene (cornflower [); phenylacetylene-d (garnet 9). (B) 1-Ethynyl-4-nitrobenzene
3
(cornflower [); 1-ethynyl-4-fluorobenzene (garnet 9); phenylacetylene (lime 2); 1-ethynyl-4-methoxybenzene (purple ꢁ); 1-ethynyl-4-dimethy-
laminobenzene (turquoise ꢁ).
outside the catalytic cycle. Both reaction order and induction
period data contribute to the following mechanistic picture of the
reaction: (1) the interaction of copper(II) and 2-picolylazide 1 is
fast and occurs prior to the entry of copper(I) into the catalytic
cycle; (2) the association between the copper(I)/azide complex
and alkyne, which leads to the formation of the triazole product,
is rate-determining; (3) the most effective catalyst may contain a
dinuclear copper core; and (4) the induction period results in the
reduction of copper(II) to copper(I) via the alkyne OHC
reaction, the rate of which is dependent on both 2-picolylazide
1 (as a base or other active roles in enhancing the rate of the
homocoupling reaction) and alkyne.
respectively, see Figures S11, S13), whereas azide 2 carries a
zero order (ꢀ0.17, Figure S12). These numbers are similar to
those recorded in the reaction between 2-picolylazide (1) and 7
in CD3CN, suggesting similarity in mechanism.
8. Deuterium Kinetic Isotope Effect (KIE) and Substituent
Effect on Phenylacetylene. The kinetic significance of alkyne
deprotonation revealed in the kinetic order determinations was
further investigated using deuterium KIE experiments and effect
of substitution on the reactivity of phenylacetylene. A primary
deuterium KIE (kH/kD) of 2.3 was observed in the reaction shown
in Scheme 3 (R = H) in CD3CN (Figure 12A). This result is
consistent with the positive kinetic order on alkyne and suggests
that deprotonation of the alkyne component is rate-determining.
The reaction involving phenylacetylene-d also sustains a
longer induction period than that of the protonated alkyne
(Figure 12A), indicating that the rate-determining step of the
alkyne OHC reaction to generate copper(I) is also the deproto-
nation of the terminal alkyne. The reaction in Scheme 3 also
shows a normal KIE in CD3OD (Figure S14), which is consistent
with alkyne deprotonation being kinetically significant. Barely
any induction period was observed in CD3OD, echoing the
observations made in fluorescence assays.
The reactivity of azide 2 is lower than that of azide 1.
Discontinuous kinetic traces of the reaction between azide 2
and alkyne 7 were collected, which challenge reaction order
determination (e.g., see Figure S10). Therefore, a more reactive
1
alkyne partner, 1-ethynyl-4-nitrobenzene, was used in the H
NMR assay (CD3CN) at an elevated temperature of 313 K for
the reactions to proceed within reasonable time frames to
minimize the probability of change in mechanism (Scheme 2).
The kinetic orders (Table 4, entries 7ꢀ9) of both 1-ethynyl-4-
nitrobenzene and Cu(OAc)2 are close to 2 (2.3 and 1.7,
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contrary to Mizuno’s system, the binding between copper(II)
and chelating azide 1 (step A) occurs prior to the rate-determin-
ing step(s) in a pre-equilibrium. This conclusion is also sup-
1
ported by the H NMR experiment where only the interaction
betweencopper(II) withazide 1 was detectedin the initial reaction
mixture (Figure 2B). Therefore, the significance of chelation is in
facilitating the interaction between azide and copper center to
the extent that the usually rapid copper(I)ꢀacetylide formation
becomes rate-determining. Consequently, an overall faster reac-
tion than those involving nonchelating azides is observed.35
Copper(II) is subsequently reduced to copper(I) via the
alkyne OHC reaction aided by azide 1 in step B (Figure 13A).
Steps B and C, which involve alkyne, are kinetically significant as
shown in both kinetic order and deuterium KIE experiments.
The intramolecular steps D and E are likely very rapid, whereas
the protonation step F could also be kinetically significant in an
aprotic solvent.
In the sequence depicted in Figure 13A, azide 1 acts as a base in
step B in aiding the formation of copper(II) acetylide prior to
diyne 9 formation. This explains the dependence of the induction
period on [1]. Azide 1 does not appear to be the base in
deprotonating alkyne in step C because of its zero order in
producing triazole 8.58 In the aprotic solvent CD3CN, alkyne 7
likely is the primary proton source in step F, which releases the
triazole product 8 and supplies the acetylide for the next cycle.
Therefore, as soon as the catalytic cycle commences, an external
base is no longer needed. Alkyne participates in steps B, C, and F,
all of which might be kinetically significant in the aprotic
CD3CN, which is consistent with the larger than second-order
dependence on alkyne.
In CH3OH (Figure 13B), a slightly different mechanistic
picture emerges. The induction period (step B0) entails the
oxidation of CH3OH, which is base (azide 1) dependent.
Copper(I) triazolide may no longer have long enough lifetime
to deprotonate alkyne because it could easily acquire proton from
the solvent CH3OH or solvent-mediated proton transfer from
protonated azide 1 (1H+) as depicted in step F0. In step C0, azide
1 helps deprotonate alkyne, which explains the fractional positive
order of azide 1 observed in CH3OH.59 Alkyne is only needed in
step C0, thus accounting for the first-order dependence.
10. The Role of Acetate. With a rough sketch of the mechan-
ism of the chelation-assisted, Cu(OAc)2-accelerated CuAAC
reaction completed (Figure 13), we turned our attention to the
structural details of the individual components involved in the
postulated mechanism and looked for answers for the extraordi-
narily fast reactions and the counterion specificity that we have
observed. There were two clues that directed our structural
studies. First, among all copper(II) salts tested, Cu(OAc)2 is
the most effective by a large margin that accelerates the reaction
between azide 4 and phenylacetylene (Table 3) in the nonoxi-
dizable solvent CH3CN. This observation suggests that in the
presence of a base, Cu(OAc)2 mediates the alkyne oxidative
homocoupling (OHC) reaction much more efficiently than do
other copper(II) salts. The observations shown in Figure 5
support this conclusion. Second, the rate of the reaction shows
a second-order dependence on Cu(OAc)2. The acceleratory
effect of acetate on copper(I)-catalyzed CuAAC reactions has
been observed anecdotally,11,60,61 and in a recent case by Hu
et al.62 been recognized to arise from the dinuclear copper core of
copper(I) acetate (CuOAc), which bears a CuꢀCu distance
(2.556 Å)63 favoring the CuAAC reaction as shown in computa-
tional studies.15
Figure 13. Postulated catalytic cycles accounting for the results of the
kinetic studies on the CuAAC reactions in Scheme 1 in CD3CN (A) and
CH3OH (B). L: Copper-binding ligand or the counterion. py: 2-Pyridyl.
Blue, orange, and purple represent the +2, +1, and +3 oxidation states of
copper, respectively. The steps of copper(I) triazolide protonation are
in green.
The time courses of various para-substituted phenylacetylene
were collected to study the effect of substitution on the reactivity of
alkyne (Scheme 3). As an electron-withdrawing group (e.g., ꢀF,
ꢀNO2) replaces hydrogen at the para position, the induction
period is significantly reduced accompanying a higher rate in the
reaction phase (Figure 12B). For 1-ethynyl-4-nitrobenzene, the
reaction completes within 10 min after mixing the reactants with
a barely noticeable induction period. The electronic effect
reported herein echoes the results by Bohlman et al. in their
mechanistic studies of the OHC reaction almost half a century
ago.56 The substituent effect provides another piece of experi-
mental evidence for the kinetic significance of alkyne deprotona-
tion in both OHC reaction in the induction period and the
CuAAC reaction in the reaction phase under the acceleration of
Cu(OAc)2 in an aprotic solvent.
9. Mechanistic Models Based on the Kinetic Measure-
ments. The kinetic profile of the CuAAC reaction between
benzylazide and phenylacetylene mediated by a dicopper(II)-
substituted silicotungstate catalyst was described by Mizuno
et al.26 A comparison of their results and ours reveals subtle
mechanistic differences between the two cases. In Mizuno’s
work, the rate has a zero order dependence on phenylacetylene
and first order in benzylazide (Table S2, entries 4ꢀ6). Further-
more, no deuterium KIE was found when using phenylacetylene-
d. This result suggests that a fast copper(I) acetylide formation
occur prior to the azide/copper(I) interaction. The following
azide binding and cycloaddition are slower, kinetically significant
steps. This conclusion is in line with the accepted ease of
copper(I)ꢀacetylide formation16,57 when a nonchelating azide
is used as the reaction partner.
The kinetic orders of chelating azide 1, alkyne 7, and Cu-
(OAc)2 reported herein offer a different scenario. In CD3CN
(Figure 13A), the zero order in chelating azide 1 indicates that in
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ꢀ
Figure 14. Chelation between copper(II) and azides 1,27,37 5,37 and 635 found in the solid-state structures. L represents a counterion (Clꢀ, NO3
SO4
2ꢀ 66 or BF4ꢀ66), a second ligand, or a water molecule.
,
,
Figure 15. ORTEP views (50% probability ellipsoids) of the asymmetric units of (A) [Cu2(1)2(OAc)4]. Selected distances (Å): Cu1ꢀN1 2.236,
Cu1ꢀCu1i 2.644, Cu1ꢀO1 1.975, Cu1ꢀO2 1.977, Cu1ꢀO3 1.960, Cu1ꢀO4 1.977. (B) [Cu2(6)2(OAc)4]. Selected distances (Å): Cu1ꢀN1 2.239,
Cu1ꢀCu2 2.641, Cu1ꢀO1 1.979, Cu1ꢀO2 1.962, Cu1ꢀO3 1.973, Cu1ꢀO4 1.954. (C) [Cu2(3)6]2ꢀ. Selected distances (Å): Cu1ꢀN4 2.219,
Cu1ꢀCu1i 2.587, Cu1ꢀO1 1.957, Cu1ꢀO2 1.965, Cu1ꢀO3 1.967, Cu1ꢀO4 1.958.
Herein, we offer a structural model that accounts for the
extraordinary reactivity and selectivity of the acetate counterion
in the CuAAC reactions involving chelating azides under appar-
ently nonreducing conditions. We will start by (1) examining the
interactions between chelating azides and Cu(OAc)2 and (2)
summarizing the key mechanistic features that have been dis-
covered by other groups. Our proposition on the unique
reactivity of Cu(OAc)2 will be subsequently presented to de-
monstrate how various pieces of experimental observations from
us and others come together.
10.1. Interactions between Chelating Azides and Copper(II)
Salts. We have demonstrated that azides 1, 5, and 6 act as
chelating ligands toward copper(II) ion (Figure 14) in single
crystal structures.27,35,37 An earlier case of coordination between
a chelating azide and copper(II) was reported by Thiel et al.64
Chelation-assisted binding between the NR of the azido group
and copper(I/II) center was proposed to enhance the electro-
philicity of the azido group which results in highly efficient
CuAAC reactions.35,37 Without chelation assistance, copper(I) has
been shown to favor Nγ, the terminal nitrogen of an azido group,
which is capable of accepting backbonding from copper(I).65
The chelation-enforced coordination between NR of the azido
which is the most effective copper(II) salt among tested thus
far that accelerates the CuAAC reaction in nonoxidizable sol-
vents, forms complexes with 1 or 6 in CH3CN (Figure 15A,B),
chelation-assisted azido coordination to copper(II) was not
observed. The common denominator of both structures is the
dinuclear “paddle-wheel” core of Cu(OAc)2 H2O,67 on which
3
the coordinated water molecules at the apical positions are
replaced by the auxiliary pyridyl group in 1 or 6 monodentately.
In complex [Cu2(3)4]n (Figure 15C), acetate ion in
[Cu2(OAc)4(H2O)2] is replaced by 3-azidopropionate (3)
where the apical positions are substituted by the azido groups
from the adjacent dinuclear [Cu2(3)4] units. Again, the dinuclear
copper(II) core remains intact. The structure propagates into a
two-dimensional network, which will be discussed in detail under
a different context. Because of the stoichiometrical nature of the
complex formation, all carboxylate moieties from 3 engage in the
formation of the paddle wheel, leaving only the azido group of 3
to bind at the apical positions. It is conceivable that when a
catalytic amount of [Cu2(OAc)4(H2O)2] is used, after exchange
of acetate by 3-azidopropionate 3, the rest of compound 3 likely
uses the carboxylate moiety, in addition to the azido group, to
bind at the apical positions68,69 to result in a structure similar to
[Cu2(1)2(OAc)4].
group and copper(II) center has been observed reꢀga6r6dless of the
2ꢀ 66
coordinating strength of the counterion (BF4
,
SO4
,
In all three structures in Figure 15, the apical NꢀCu bonds are
ꢀ 37
NO3
,
and Clꢀ27,35,37). Unexpectedly, when Cu(OAc)2,
rather long (2.22ꢀ2.24 Å), indicating relatively weak and
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Figure 16. Models of dinuclear pathways for azide/alkyne ligation. L: A bridging ligand or counterion (e.g., acetate, acetylide, or iodide) that is not
participating in the redox reaction, that is, no electron exchange between L and copper. The formal charges on individual atoms are noted. All bonds
surrounding L are considered to be coordinative rather than covalent for the ease in formal charge calculations. Orange, copper(I); purple, copper(III).
The carbon and nitrogen atoms that engage in bonding are numbered 2 and 3, respectively.
Table 5. CuꢀCu Distances in Various Copper Salts or Complexes Evaluated in CuAAC Reactions
dicopper(II) silicotungstate26
Cu(OAc)2
[RꢀCtCꢀCu]n
CuOAc62
27
33
CuꢀCu/Å
oxidation state
induction period
2.8176
+2
2.64 (this work)
2.5ꢀ2.877
+1
no
2.5563
+1
+2
yes
yes
no
dynamic association that facilitates turnover. The CuꢀCu dis-
tances (2.59ꢀ2.64 Å) are within the range of a large collection of
known apically substituted copper(II) acetate structures.70 Both
copper(II) centers in a paddle wheel are coordinatively saturated
with six ligands each (counting the other copper(II) center) in an
octahedral geometry, leaving no room for azido chelation. In the
following subsections, our explanation on the unique role of
Cu(OAc)2 in the chelation-assisted, copper(II)-accelerated
CuAAC reaction will be presented on the basis of the kinetic
and structural data collected by us and others.
copper(III)ꢀalkenylidene moiety, is deemed an unlikely high
energy species.14 Structures I and III are consistent with the
computed dicopper(I,III) μ-alkenylidene intermediate,14,15
whereas the larger ring size in structure II alleviates the ring
strain of the endocyclic copper(III)ꢀalkenylidene. One observa-
tion worth noting is that only one copper(I) center is needed for
redox chemistry. The oxidation state of the other copper center is
unaltered during the ligation step. In our subsequent discussions
on the role of acetate under the copper(II)-accelerated CuAAC
reactions, we will refer back to the structural models shown in
Figure 16.
10.2. Dinuclear Copper(I) Catalytic Center. There is a con-
sensus on the second-order dependence on copper(I) of ligand-
free CuAAC reactions,13ꢀ15,26,36,71 which implicates the involve-
ment of a highly active dinuclear copper catalyst. It should be
noted that the active dinuclear species is likely in equilibrium with
monomeric copper species,72ꢀ74 which is the premise for the
reaction to show a second-order dependence in copper. If a stable
dinuclear copper catalyst that does not dissociate into mono-
nuclear species is involved, a first order should result as reported
in the dicopper(II) silicotungstate system by Mizuno et al.26 Two
structural models (A and B in Figure 16) have been proposed in a
number of articles to account for the second-order dependence
on copper in CuAAC reactions.13,16,17,28,41,75 Alkyne and azide
are bonded to different copper(I) centers in A (Figure 16),
whereas a single copper(I) center activates both alkyne and azide
components in B. The two structural models may interconvert in
an equilibrium where the copper(I) acetylide bond alternates
from σ (solid bond) to π (dashed bond). Depending on which
copper(I) is oxidized in the C2ꢀN3 ligation step, four inter-
mediate (or transition state) structures (IꢀIV) may result.
Structure IV, which contains a highly strained endocyclic
For the cooperative dinuclear catalysis depicted in Figure 16 to
work, an important parameter is the CuꢀCu distance that is
appropriate for the formation of the (μ, η1,2)-CtCfCu2 in
structures A and B (Figure 16). A CuꢀCu distance in the range
of 2.54ꢀ2.64 Å was computed by Ahlquist and Fokin15 in a
dinuclear transition state en route to the matallacycle intermedi-
ate similar to structure III (Figure 16). The dinuclear copper
catalysts that have shown exceptional activities under conven-
tional solution phase CuAAC reactions are included in Table 5.
All four dinuclear copper reagents have CuꢀCu distances within
or close to the computed range. The two copper(II) reagents
(columns 1 and 2) experience induction periods in nonoxidizable
solvents to generate copper(I) catalytic species via oxidative
homocoupling (OHC) of the alkyne component. In comparison,
the dismally low activity of other copper(II) salts in CuAAC
reactions shown in Table 3 suggests that a dinuclear copper(II)
core of an appropriate CuꢀCu distance be favorable for the
OHC reactions to afford the much needed copper(I).78 In the
following text, we will describe the mechanistic synergy between
the OHC and the CuAAC reactions as well as the important role
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Figure 17. Postulated Glaser/Eglinton coupling sequence enabled by Cu(OAc)2/pyridine complex. A delocalized negative charge is implied in the
drawing of the acetate.
Figure 18. Mechanistic model of the 2-picolylazide (1) involved, Cu(OAc)2-accelerated CuAAC reaction. Structure I could be generated via the OHC
sequence depicted in Figure 17 in an induction period. Orange, +1 oxidation state; purple, +3 oxidation state. Formal charges on individual atoms are
noted. CuA: Oxidation state is undefined. See text.
that a chelating azide such as 2-picolylazide 1 plays in this
Cu(OAc)2-mediated OHC/AAC sequence.
single crystal structures in the CCDC database, PYCUAC01ꢀ05),
which is the active ingredient in an OHC reaction in the method
of Eglinton.79,80 The functions of pyridine in the Eglinton
coupling include deprotonation of alkyne to acetylide,81 which
displaces two acetate to afford μ2,η1,2-CtCfCu2-containing III
(Figure 17, step B). A formal metathesis process follows to release
the diyne product56,82 and the dinuclear copper(I) acetate (step
C).63,83,84 On the basis of our observations on the OHC in the
10.3. The Mechanistic Picture Involving Cu(OAc)2 and the
Chelating 2-Picolylazide. The induction process to generate
copper(I) in a nonoxidizable solvent such as CH3CN is
the OHC reaction. The structures of [Cu2(1)2(OAc)4] and
[Cu2(6)2(OAc)4] (Figure 15) are isomorphic to that of the 1:1
complex of Cu(OAc)2 and pyridine (structure II in Figure 17, five
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Figure 19. Known structural modes for carboxylate-bridged dinuclear copper complexes. Left, copper(II) acetate; middle, mixed-valency copper(II)/
copper(I) acetate; right, copper(I) acetate.
The two copper centers in the model presented in Figure 18
carry different functions. CuB is oxidized to copper(III) upon the
formation of the metallacycle intermediate. This redox reaction
accounts for the regiospecificity of the CuAAC reaction where
only 1,4-substituted 1,2,3-triazole is produced.1 CuA holds the
azide component in position and as a Lewis acid increases the
electrophilicity of the azido group. The oxidation state of CuA
does not change over the course of the reaction. One may
surmise that a stronger Lewis acid than copper(I) in place of CuA
may increase the reactivity of the azido group in a CuAAC
reaction. A copper(II) center that is more Lewis acidic than
copper(I) is the most convenient choice.
10.4. Possible Involvement of a Highly Active Mixed Valency
Copper(II)/Copper(I) Dinuclear Catalyst? A mixed-valency
copper(II)/copper(I) acetate may fit the bill to activate alkyne
and azide at different copper centers (as shown in II and II0 in
Figure 18, when CuA has +2 oxidation state). Copper(I) is
Figure 20. The dependence of reaction time course on sodium
ascorbate (NaAsc). Conditions: [1] = 10 mM, [7] = 10 mM,
necessary for the redox step in the mechanism, whereas copper-
(II) activates the azido group as a strong Lewis acid. Carboxylate-
bridged mixed-valency copper(II)/copper(I) complexes are
known.85 Its general structure is depicted in Figure 19 along
with copper(II) and copper(I) acetates based on reported single
crystal structures.86ꢀ92 In most cases, both copper centers adopt
square planar geometry capped by a carboxylate bridge. The
apical carboxylate may be displaced by other ligands,91 for
example, by azide and alkyne, to afford structure II in Figure 18.
The charges on most carboxylate-bridged [Cu2]3+ cores are fully
delocalized where each copper takes a formal +1.5 oxidation
number. However, when the two copper centers are asymme-
trically substituted as in structure II (Figure 18), the charge
density may redistribute to best accommodate the two electro-
nically different apical ligands. Therefore, it is plausible that such
an asymmetric [Cu2]3+ core may possess distinct reactivities of
both copper(II) (a Lewis acid) and copper(I) (a soft, back-
bonding cation).
We have not captured the mixed-valency dinuclear copper
catalyst in either free or substrate-bound form (II and II0 in
Figure 18). However, the indirect evidence that supports the
proposition that copper(II) is not merely a precursor to the
copper(I) catalyst but actively engages in catalyzing the reaction
as a Lewis acid is shown in Figure 20. The reaction between
alkyne 7 and 2-picolylazide 1 aided by Cu(OAc)2 endures an
induction period of ∼40 min (case 1). With the addition of 4 mol
equiv of sodium ascorbate to copper(II), the reaction proceeds
immediately after mixing without an induction period (case 2).
However, the rate of the reaction (the slope of the curve) is
consistently lower than the rate of the reaction phase of case 1.
When a substoichiometric amount of sodium ascorbate is added
into the reaction mixture (case 3), not only the induction period
[Cu(OAc)2 H2O] = 1 mM, [NaAsc] = 0 (lime 2), [NaAsc] = 4 mM
3
(garnet 9), [NaAsc] = 0.25 mM (cornflower [).
induction periods of the CuAAC reaction, the deprotonation step
B is rate-determining.
The mechanistic model for Cu(OAc)2-accelerated CuAAC
reaction involving 2-picolylazide 1 is depicted in Figure 18. In the
presence of a terminal alkyne, [Cu2(1)2(OAc)4] (Figure 15A)
may also rapidly transform alkyne to diyne via the sequence
shown in Figure 17 to afford [Cu2(1)2(OAc)2] (structure I in
Figure 18). With two acetate counterions removed, [Cu2(1)2(OAc)2]
has open coordination positions for the azido group to associate
with copper(I), while an alkyne molecule upon deprotonation by
1 also binds a copper(I) center to afford structures II or II0
(Figure 18). The azide and alkyne components associate with
different copper(I) centers in structure II. Intramolecular oxida-
tive metallacycle formation affords a seven-membered ring
containing a copper(III)ꢀalkenylidene. Subsequently the rapid
reductive ring contraction affords copper(I) triazolide, which
upon protonation results in the triazole product.
If both azide and alkyne components bind the same copper(I)
center, structure II0 results (Figure 18). The second copper(I)
center participates in the reaction by forming a π-complex
with the acetylide. A six-membered metallacycle containing a
μ-alkenylidene with minimal strain is afforded in the next step.
Subsequent ring contraction followed by protonation completes
the triazole formation. On the basis of the kinetic data, the
formation of structure II or II0 (Figure 18), which involves
deprotonation of alkyne, is rate-determining. The feasibility of
either pathway may be interrogated computationally, which will
be addressed in a future study.
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the highly catalytic species has a mixed-valency dinuclear
copper core.
11. Evolution of the Structure of the Copper-Containing
Catalyst. In the above and other mechanistic analyses of CuAAC
reactions, conclusions are drawn on the basis of data such as
kinetic orders determined over the initial phase of the reaction, or
the CuꢀCu distance of a dinuclear catalyst (or a precatalyst) that
is introduced at the onset of the reaction. However, kinetic order,
CuꢀCu distance, ratio of reactants to catalyst, and other
mechanistically relevant parameters do likely change over the
16
course of the reaction. Discretion must be used when the
mechanistic conclusions drawn on the basis of the data from
the initial phase are extended to the full duration of the reaction.
The versatility of copper coordination chemistry renders the
CuAAC reaction an excellent case study where the structure of
the (pre)catalyst, in this case Cu(OAc)2, may evolve as the
reaction proceeds, thus altering the mechanism.93 For example,
during an attempt to prepare the Cu(OAc)2 complex with
2-picolylazide 1 in CH3OH, [Cu4(OAc)4(OCH3)4] (Figure 21),
a known tetranuclear copper(II) cluster structure,94,95 was isolated
in single crystal forms after 3ꢀ4 days. In the absence of an alkyne
reaction partner, compound 1 deprotonates CH3OH over time to
methoxide, which displaces acetate to afford the Cu4 cluster
structure. If the time scale of a CuAAC reaction is longer than that
of this transformation, a change in reaction mechanism over the
course of the reaction is expected.
Figure 21. A tetranuclear copper(II) cluster structure [Cu4(OAc)4-
(OCH3)4] (50% probability ellipsoids) isolated after mixing Cu-
(OAc)2 H2O and azide 1 in CH3OH. Selected distances (Å): Cu1ꢀO1
3
1.973, Cu1ꢀO3 1.938, Cu1ꢀO5 1.935, Cu1ꢀO5i 1.924, Cu1ꢀCu2
2.958, Cu1ꢀCu1i 2.987, Cu1ꢀO2 (opposite to Cu2 on the axial
position; not shown) 2.586.
The second example highlights how copper/alkyne interac-
tion transforms the structure of Cu(OAc)2. In the absence of an
azide component, 3,3-dimethylbutyne slowly reacts with Cu-
(OAc)2 in CH3OH to result in a copper(I)14 cluster and the
homocoupled diyne product (Figure 22). Evidently, the strong
affinity between copper(I) and acetylide leads to the disintegra-
tion of the dinuclear Cu(OAc)2 structure. Phenylacetylene was
initially used in this experiment, which afforded an intractable
yellow precipitate.77 3,3-Dimethylbutyne is known to afford
discrete alkynyl/copper(I) cluster structures because the steric
effect imposed by the t-butyl group prevents the aggregation of
copper(I)ꢀacetylide.77,96,97 This copper(I)14 cluster structure is
interesting in its own right.97 The relevance of this structure to
the current work is that in the absence of an azide, or in the
presence of an azide substrate with low reactivity, copper centers
preferentially interact with the alkyne component to transform to
cluster type structures often with impaired catalytic reactivity.
’ CONCLUSIONS
A mechanism is proposed for the chelation-assisted, Cu-
(OAc)2-accelerated azideꢀalkyne cycloaddition reaction on
the basis of kinetic and structural investigations. The high
reactivity of chelating azides, such as 2-picolylazide, is attributed
to the rapid copperꢀazido interaction that occurs prior to
copper(I) acetylide formation. Under this circumstance, the
deprotonation of alkyne becomes rate-determining, as shown
in deuterium KIE and substituent effect experiments. The
specificity of Cu(OAc)2 in the reported reaction is attributed
to its optimal CuꢀCu distance in the dinuclear copper(II) core
in mediating both the alkyne oxidative homocoupling and the
CuAAC reactions. The two copper centers in the proposed
dinuclear catalyst are carrying different functions: one is a Lewis
acid and the other is a redox active copper(I) center. This
observation leads us to speculate that a copper(II)/copper(I)
mixed valency dinuclear species would be highly catalytic in
Figure 22. (A) A copper(I)14 cluster structure isolated via mixing
Cu(OAc)2 H2O with 3,3-dimethylbutyne in CH3OH. (B) The cocrys-
3
tallized 2,2,7,7-tetramethylocta-3,5-diyne.
disappears, but the rate of the reaction is enhanced over both
copper(II)- and copper(I)-accelerated cases. These data sug-
gest that the synergistic effect of copper(I) and copper(II) leads
to the high activity of the catalyst present in case 3. Presumably
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CuAAC reactions, which is supported by the extraordinary
CuAAC reactivity of a partially reduced Cu(OAc)2 system
involving the chelating 2-picolylazide. In addition to continuing
the hunt for intermediates in the chelation-assisted, Cu(OAc)2-
accelerated variant of the CuAAC reaction, computational inter-
rogation of the proposed mechanism will be conducted in the
near future. This work may lead to the examination of the
possible mechanistic significance of mixed valency dinuclear
copper catalysts in other copper-mediated reactions.
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other redox couple(s) in the reaction mixture. Therefore, there is always
a certain level of copper(I) presence under any circumstance. For
example, in water, copper(I) may exist at ppb level per mole of
copper(II) as estimated using the Nerst equation. An extremely low
level of copper(I) salt may indeed do wonders. Buchwald, S. L.; Bolm, C.
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observed under the copper(II)-promoted conditions that is compar-
able to or even higher than those under the typical copper(I)-catalyzed
conditions cannot be simply explained by the extremely high reactivity of
a miniscule amount of copper(I) contaminant. Furthermore, we and
others have presented evidence for the transformation of copper(II) to
copper(I) over the course of a copper(II)-accelerated CuAAC reaction.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, char-
b
acterization of new compounds, and additional figures. This
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
lzhu@chem.fsu.edu
(27) Brotherton, W. S.; Michaels, H. A.; Simmons, J. T.; Clark, R. J.;
Dalal, N. S.; Zhu, L. Org. Lett. 2009, 11, 4954–4957.
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(29) Copper(I)/copper(III) redox pair has been recognized to be
involved in copper-mediated cross coupling reactions. See refs 29 and
30: Hartwig, J. Organotransition Metal Chemistry - From Bonding to
Catalysis; University Science Books: Sausalito, CA, 2010.
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’ ACKNOWLEDGMENT
This work was supported in part by NIGMS (R01GM081382)
and NSF (CHE0809201). We thank Professor Ronald Breslow
(Columbia University) for suggesting the deuterium kinetic
isotope effect experiment.
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