Chelation-assisted, copper(II)-acetate-accelerated azide-alkyne cycloaddition

Article abstract of DOI:10.1021/jo101305m

We described in a previous communication a variant of the popular Cu ^I-catalyzed azide-alkyne cycloaddition (AAC) process where 5 mol % of Cu(OAc)₂ in the absence of any added reducing agent is sufficient to enable the reaction. 2-Picolylazide (1) and 2-azidomethylquinoline (2) were found to be by far the most reactive carbon azide substrates that convert to 1,2,3-triazoles in as short as a few minutes under the discovered conditions. We hypothesized that the abilities of 1 and 2 to chelate Cu^II contribute significantly to the observed high reaction rates. The current work examines the effect of auxiliary ligands near the azido group other than pyridyl for Cu^II on the efficiency of the Cu(OAc)₂-accelerated AAC reaction. The carbon azides capable of binding to the catalytic copper center at the alkylated azido nitrogen in a chelatable fashion were indeed shown to be superior substrates under the reported conditions. The chelation between carbon azide 11 and Cu^II was demonstrated in an X-ray single-crystal structure. In a limited set of examples, the ligand tris(benzyltriazolylmethyl) amine (TBTA), developed by Fokin et al. for assisting the original Cu ^I-catalyzed AAC reactions, also dramatically enhances the Cu(OAc)₂-accelerated AAC reactions involving nonchelating azides. This observation leads to the hypothesis of an additional effect of chelating azides on the efficiencies of Cu(OAc)₂-accelerated AAC reactions, which is to facilitate the rapid reduction of Cu^II to highly catalytic Cu^I species. Mechanistic studies on the AAC reactions with particular emphasis on the role of carbon azide/copper interactions will be conducted based on the observations reported in this work. Finally, the immediate utility of the product 1,2,3-triazole molecules derived from chelating azides as multidentate metal coordination ligands is demonstrated. The resulting triazolyl-containing ligands are expected to bind with transition metal ions via the N(2) nitrogen of the 1,2,3-triazolyl group to form nonplanar coordination rings. The Cu^II complexes of bidentate T1 and tetradentate T6 and the Zn^II complex of T6 were characterized by X-ray crystallography. The structure of [Cu(T1)₂(H₂O) ₂](ClO₄)₂ reveals the interesting synergistic effect of hydrogen bonding, π-π stacking interactions, and metal coordination in forming a one-dimensional supramolecular construct in the solid state. The tetradentate coordination mode of T6 may be incorporated into designs of new molecule sensors and organometallic catalysts.

Full text of DOI:10.1021/jo101305m

pubs.acs.org/joc
Chelation-Assisted, Copper(II)-Acetate-Accelerated
Azide-Alkyne Cycloaddition
Gui-Chao Kuang, Heather A. Michaels, J. Tyler Simmons, Ronald J. Clark, and Lei Zhu*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306-4390
lzhu@chem.fsu.edu
Received July 2, 2010
We described in a previous communication a variant of the popular CuI-catalyzed azide-alkyne
cycloaddition (AAC) process where 5 mol % of Cu(OAc)2 in the absence of any added reducing agent
is sufficient to enable the reaction. 2-Picolylazide (1) and 2-azidomethylquinoline (2) were found to be
by far the most reactive carbon azide substrates that convert to 1,2,3-triazoles in as short as a few
minutes under the discovered conditions. We hypothesized that the abilities of 1 and 2 to chelate CuII
contribute significantly to the observed high reaction rates. The current work examines the effect of
auxiliary ligands near the azido group other than pyridyl for CuII on the efficiency of the Cu(OAc)2-
accelerated AAC reaction. The carbon azides capable of binding to the catalytic copper center at the
alkylated azido nitrogen in a chelatable fashion were indeed shown to be superior substrates under
the reported conditions. The chelation between carbon azide 11 and CuII was demonstrated in an
X-ray single-crystal structure. In a limited set of examples, the ligand tris(benzyltriazolylmethyl)-
amine (TBTA), developed by Fokin et al. for assisting the original CuI-catalyzed AAC reactions, also
dramatically enhances the Cu(OAc)2-accelerated AAC reactions involving nonchelating azides. This
observation leads to the hypothesis of an additional effect of chelating azides on the efficiencies of
Cu(OAc)2-accelerated AAC reactions, which is to facilitate the rapid reduction of CuII to highly
catalytic CuI species. Mechanistic studies on the AAC reactions with particular emphasis on the role
of carbon azide/copper interactions will be conducted based on the observations reported in this
work. Finally, the immediate utility of the product 1,2,3-triazole molecules derived from chelating
azides as multidentate metal coordination ligands is demonstrated. The resulting triazolyl-containing
ligands are expected to bind with transition metal ions via the N(2) nitrogen of the 1,2,3-triazolyl
group to form nonplanar coordination rings. The CuII complexes of bidentate T1 and tetradentate T6
and the ZnII complex of T6 were characterized by X-ray crystallography. The structure of
[Cu(T1)2(H2O)2](ClO4)2 reveals the interesting synergistic effect of hydrogen bonding, π-π stacking
interactions, and metal coordination in forming a one-dimensional supramolecular construct in the
solid state. The tetradentate coordination mode of T6 may be incorporated into designs of new
molecule sensors and organometallic catalysts.
Introduction
developed for specific substrate classes and environmental
constraints.2 A procedure for an AAC reaction typically
consists of the following components;copper source
(e.g., CuII salts,3 CuI salts4), reducing agent (e.g., sodium
As one of the most operationally simple organic transfor-
mations, the CuI-catalyzed azide-alkyne cycloaddition
(AAC) reaction has facilitated advances in many areas of
science.1 The rich, yet elusive mechanistic variability of this
reaction has engendered a large number of procedures
(2) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952–3015.
(3) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2596–2599.
(4) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057–3064.
(1) Finn, M. G.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1231–1232.
6540 J. Org. Chem. 2010, 75, 6540–6548
Published on Web 08/31/2010
DOI: 10.1021/jo101305m
r
2010 American Chemical Society

Kuang et al.
JOCArticle
FIGURE 2. (A) Cu(OAc)2-accelerated AAC “click” reaction.
(B) 2-Picolylazide forms a complex with CuCl2.13 The formal
charges on Nβ and Cu are noted. (C) Simplified chelation model
of the intermediate prior to the metallacycle formation en route to
the 1,4-substituted 1,2,3-triazole.
multidentate product molecules, we discovered that Cu(OAc)2
accelerates the AAC reaction in organic solvents, particularly in
alcohols without deliberate addition of a reducing agent such as
sodium ascorbate (see an example in Figure 2A).13,16 We
postulated that in this procedure the catalytic CuI species
emerges in a short induction period via reducing Cu(OAc)2 by
alcoholic solvent or terminal alkyne in an oxidative homocou-
pling reaction.13 The direct observations of the homocoupled
products and the formation of aldehyde species under similar
AAC conditions by Mizuno et al.17 and Heaney et al.18,19 are in
agreement with our hypothesis on the catalyst-producing induc-
tion process.
In addition to the absence of an added reducing agent,
consistent observations suggest that 2-picolylazide (1) and
2-azidomethylquinoline (2) are exceptional substrates under
the CuII-accelerated conditions, where the nature of the
alkyne component carries less impact in the efficiency of
the reaction (unpublished observations). Due to the ability of
these two carbon azides to chelate CuII (Figure 2B; the X-ray
crystal structure was reported in ref 13), the catalytic CuI
center generated via the reductive induction period is biased
to bind at the alkylated nitrogen (NR in Figure 2B) of the
azido group (CuI in the absence of chelation effect may favor
coordination at the terminal Nγ position of the azido group,
as shown by Dias et al.20). We hypothesized that the electro-
philicity of the azido group is dramatically enhanced via
chelation-assisted binding between CuI and NR, thus accel-
erating the nucleophilic attack by the copper acetylide and
the subsequent formation of the metallacycle intermediate
(see a structural model prior to the metallacycle formation in
Figure 2C) in the rate-determining step (red step in Figure 1).3
In this work, to test whether the chelation-elevated reactivity
of carbon azide in Cu(OAc)2-accelerated AAC reactions
FIGURE 1. Simplified mechanistic proposal by Sharpless and
Fokin et al.3 The CuI-acetylide formation steps are marked blue;
the formation of six-membered metallacycle is marked red. L: a
ligand or a counterion associated with CuI/II. Not shown is the
possible bimolecular pathway between CuI-acetylide and carbon
azide to afford the metallacycle.
ascorbate,3 elemental copper,5 phosphorus(III) agents,6 elec-
trochemical reduction,7 etc.), solvent (aqueous, organic, or
mixed), base (presumably for facilitating copper acetylide
formation2), and accelerating ligand (various polyaza
ligands).8,9 One major focus in the method development of
CuAAC reactions has been to find conditions that are suited
to various substrate classes to rapidly generate CuI-acetylide
(blue steps in Figure 1) while protecting the þ1 oxidation
state of the copper catalyst.10 In a simplified, generally
accepted mechanistic model (Figure 1),3 CuI-acetylide sub-
sequently forms a complex with the carbon azide substrate or
reacts with it bimolecularly in the rate-determining step11,12
to afford the metallacycle intermediate (red step in Figure 1)
en route to the 1,2,3-triazole product. In this proposed
mechanism, the involvement of CuI oxidation state is re-
quired. Therefore, when a CuII salt is used as the precatalyst,
judicious choice for a reducing agent has to be made in order
to generate and sustain an adequate amount of the highly
catalytic CuI species without interfering with other func-
tional groups in the reaction system.
Our group is interested in developing 1,2,3-triazolyl-contain-
ing polydentate metal coordination ligands.14,15 Motivated
by the need to develop simple protocols for CuAAC reactions
to ease the purification of highly polar triazolyl-containing
(5) Brik, A.; Muldoon, J.; Lin, Y.-C.; Elder, J. H.; Goodsell, D. S.; Olson,
A. J.; Fokin, V. V.; Sharpless, K. B.; Wong, C.-H. ChemBioChem 2003, 4,
1246–1248.
(6) Wang, Q.; Chan, T. R.; Higraf, R.; Fokin, V. V.; Sharpless, K. B.;
Finn, M. G. J. Am. Chem. Soc. 2003, 125, 3192–3193.
(7) Hong, V.; Udit, A. K.; Evans, R. A.; Finn, M. G. ChemBioChem 2008,
9, 1481–1486.
(8) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org. Lett.
2004, 6, 2853–2855.
(9) Rodionov, N. O.; Presolski, S. I.; Dıaz, D. D.; Fokin, V. V.; Finn,
M. G. J. Am. Chem. Soc. 2007, 129, 12705–12712.
(10) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302–1315.
(11) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.;
Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210–216.
(12) Ahlquist, M.; Fokin, V. V. Organometallics 2007, 26, 4389–4391.
(13) Brotherton, W. S.; Michaels, H. A.; Simmons, J. T.; Clark, R. J.;
Dalal, N. S.; Zhu, L. Org. Lett. 2009, 11, 4954–4957.
(14) Huang, S.; Clark, R. J.; Zhu, L. Org. Lett. 2007, 9, 4999–5002.
(15) Michaels, H. A.; Murphy, C. S.; Clark, R. J.; Davidson, M. W.; Zhu,
L. Inorg. Chem. 2010, 49, 4278–4287.
(16) Earlier observations that Cu(II) is capable of enabling AAC reac-
tions appeared in the following reports. Differing from our conclusions,
however, Cu(II) was postulated as the directly participating catalytic species
in AAC reactions without being reduced to Cu(I) in these reports: (a) Reddy,
K. R.; Rajgopal, K.; Kantam, M. L. Synlett 2006, 957–959. (b) Fukuzawa,
S.-I; Shimizu, E.; Kikuchi, S. Synlett 2007, 2436–2438. (c) Reddy, K. R.;
Rajgopal, K.; Kantam, M. L. Catal. Lett. 2007, 114, 36–40. (d) Song, Y.-J.;
Yoo, C.; Hong, J.-T.; Kim, S.-J.; Son, S. U.; Jang, H.-Y. Bull. Korean Chem.
Soc. 2008, 29, 1561–1564. (e) Namitharan, K.; Kumaaraja, M.; Pitchumani,
K. Chem.;Eur. J. 2009, 15, 2755–2758.
(17) Kamata, K.; Nakagawa, Y.; Yamaguchi, K.; Mizuno, N. J. Am.
Chem. Soc. 2008, 130, 15304–15310.
(18) Buckley, B. R.; Dann, S. E.; Harris, D. P.; Heaney, H.; Stubbs, E. C.
Chem. Commun. 2010, 46, 2274–2276.
(19) Buckley, B. R.; Dann, S. E.; Heaney, H. Chem.;Eur. J. 2010, 16,
6278–6284.
(20) Dias, H. V. R.; Polach, S. A.; Goh, S.-K.; Archibong, E. F.;
Marynick, D. S. Inorg. Chem. 2000, 39, 3894–3901.
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TABLE 1. Cu(OAc)2-Accelerated AAC Reactions of Chelating Azides with N-Containing Auxiliary ligandsa
aGeneral conditions: azide (0.2 mmol), alkyne (0.2-0.22 mmol), t-BuOH (0.5 mL), and Cu(OAc)2 (25 μL, 0.4 M solution in H2O, 10 μmol). bPy =
c
2-pyridyl. Reaction time refers to the time it takes for the azide substrate to be undetectable by TLC. dIsolated yield after purification by column
chromatography.
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observed in compounds 1 and 2 is generally applicable, we
examined the efficiencies of the AAC reactions involving a
series of carbon azides whose NR may bind CuII via chela-
tion. In the following section, we report (1) the reactivities of
various carbon azides designed to chelate CuII, (2) the ligand
acceleration effect on the efficiencies of the AAC reactions
involving nonchelating azides in the presence of Cu(OAc)2,
and (3) the utility of the triazole products derived from the
chelating azides as new multidentate metal coordination
ligands. The conclusion from the first two points leads to
testable mechanistic hypothesis on the Cu(OAc)2-acceler-
ated AAC reactions which is currently under investigation in
our laboratory.
FIGURE 3. ORTEP (50% ellipsoids) diagrams of [Cu2(11)2Cl4].
Selected distances (A): Cu1-Cl1 2.419, Cu1-Cl2 2.245, Cu1-N1
2.201, Cu1-N4 1.994, Cu-Cl1a 2.317, N1-N2 1.243, N2-N3
1.123.
Results and Discussion
1. Reactivities of Chelating Carbon Azides with N-Containing
Auxiliary Ligands. Various carbon azides containing neigh-
boring nitrogen donor ligands (1-11) were prepared. The
yields of the AAC reactions in t-BuOH involving these azides
in the presence of 5 mol % of Cu(OAc)2 without the addition
of reducing agent are shown in Table 1. The azides capable of
chelating CuII between the NR of the azido group and a
nitrogen-based auxiliary ligand to afford five-membered rings
(1-7) undergo rapid AAC reactions (from minutes up to 3 h)
with high yields (Table 1, entries 1, 3-6, 8-10). Nitrogen
donor ligands of sp2 or sp3 hybridization yield no significant
difference in reactivity. The results of two control experiments
emphasize the significance of chelation over the basicity of
the amino/pyridyl-based auxiliary ligands. First, the AAC
reactions between 1-azidooctane and p-ethynylanisole in the
presence of 1 molar equiv of pyridine (entry 2) or N-methyl-
pyrrolidine (entry 7) proceed rather sluggishly. Second, the
completion times for reactions between 2-picolylazide (1) or
N-(2-azidoethyl)pyrrolidine (4) and phenylacetylene are pro-
gressively longer as pyridine or N-methylpyrrolidine of in-
creasing amounts were added to compete in coordination to
CuII (see Supporting Information). When the auxiliary ligand
is a 2-fluoropyridyl group (entries 11 and 12), the reactions
take a considerably longer time to reach completion. Presum-
ably, the donor strength of the pyridyl nitrogen is weakened by
the presence of the electron-withdrawing fluorine substituent.
Azides 10 and 11 are able to chelate with CuII to form six-
membered rings. Azide 11 reacts smoothly to afford the
triazole products (Table 1, entries 15 and 16). More time
was required for 10 to reach complete conversion in the AAC
reactions (Table 1, entries 13 and 14), which may be in part
attributed to the impaired binding of 10 to the copper center
due to the presence of a longer alkyl chain.
was observed,13,22 the CuII centers in this dimeric complex
adopt a distorted trigonal bipyramidal form where the
pyridyl nitrogen (N4 in Figure 3) and one of the bridging
chlorides (Cl1a) are at the apical positions. A [Cu2Cl2]
rectangle core results from the ∼90° angle of Cl1-Cu1-Cl1a.
The six-membered chelation ring is in a boat conformation.
The bond angles around the alkylated nitrogen N1 are ∼120°,
suggesting a sp2-hybridized N1.
2. Reactivities of Carbon Azides with O- and S-Containing
Auxiliary Ligands. Carbon azides containing potentially che-
lating oxygen- and sulfur-based donor ligands were evaluated.
The reactions between the neutral carboxylic acids 12 and 13
and p-ethynylanisole proceed very sluggishly. In the presence
€
of 1 molar equiv of Hunig’s base (N,N-diisopropylethylamine),
the deprotonated azidocarboxylates undergo rapid AAC reac-
tions aided by 5 mol % of Cu(OAc)2 (Table 2, entries 1 and 2).
As shown in a control experiment, the reaction between
1-azidooctane and p-ethynylanisole was affected little by the
€
addition of Hunig’s base. After 55 h, the isolated reaction
yields in the presence and absence of Hunig’s base were only 25
€
and 19%, respectively. Evidently, in entries 1 and 2 (Table 2),
€
the role of Hunig’s base is restricted to deprotonation of the
azidocarboxylic acids. It is at best only marginally involved in
the deprotonation of the alkyne and/or CuII reduction. This
observation reaffirms that chelation of CuII enabled by car-
boxylate formation is instrumental in the rate acceleration.
Carbon azides containing ether- and sulfide-based auxili-
ary donors were allowed to react over extended periods of
time (15-24 h) with poor yields (Table 2, entries 3-6). The
weaker Lewis basicities of the oxygen and sulfur donors in
ethers and sulfides than that of amino/pyridyl groups when
paired with the Lewis acidic CuII may result in weak binding,
hence insufficient activation of the azido group in the AAC
reactions.
3. Assisting Ligand Effect in the Cu(OAc)2-Accelerated
Process. During the development of CuI-catalyzed AAC reac-
tions, the likelihood of autocatalysis to result in rate accelera-
tion was considered by Fokin, Finn, and others.8,9,23,24 Similar
autocatalytic processes might operate in the Cu(OAc)2-accel-
erated AAC reactions where the bidentate triazole product
serves as an accelerating ligand. Three bidentate triazole
The chelating ability of azide 11 was revealed by the X-ray
crystal structure of its complex with CuCl2 (Figure 3). Green,
air-stable [Cu2(11)2Cl4] crystallizes in P2(1)/c space group via
vapor diffusion of diethyl ether to a methanolic solution of 11
and CuCl2 at equal molar ratio.21 The NR of the azido group in
conjunction with the pyridyl nitrogen binds CuII to form a
six-membered chelation ring. In contrast to our previously
reported [Cu2(1)2Cl4], where the square pyramidal CuII geometry
(21) CuCl2 was shown to be a capable precatalyst under the crystal-
lization conditions. Azide 11 and phenylacetylene in the presence of 5 mol %
of CuCl2 in CH3OH convert readily to the triazole product.
(22) See an earlier example: Barz, M.; Herdtweck, E.; Thiel, W. R.
Angew. Chem., Int. Ed. 1998, 37, 2262–2265.
(23) Lewis, W. G.; Magallon, F. G.; Fokin, V. V.; Finn, M. G. J. Am.
Chem. Soc. 2004, 126, 9152–9153.
(24) Donnelly, P. S.; Zanatta, S. D.; Zammit, S. C.; White, J. M.;
Williams, S. J. Chem. Commun. 2008, 2459–2461.
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TABLE 2. AAC Reactions of Azides with O and S Auxiliary Donorsa
aGeneral conditions: azide (0.2 mmol), alkyne (0.2-0.22 mmol), t-BuOH (0.5 mL), and Cu(OAc)2 (25 μL, 0.4 M solution in H2O, 10 μmol).
bN,N-Diisopropylethylamine (0.2 mmol) was added. cIsolated yield after purification by column chromatography.
compounds derived from 2-picolylazide (T1, T18, and T19)25
were applied as additives in the AAC reactions that barely
proceed in the presence of 5 mol % of Cu(OAc)2 (Table 3,
entries 1-6). The ligands were found to moderately accelerate
the AAC reactions.26 The moderate, yet consistent accelerating
effect of bidentate triazoles suggests the possibility of auto-
catalysis.
In a study by Fokin et al., a polytriazole compound,
tris(benzyltriazolylmethyl)amine (TBTA), was found to be
an outstanding cocatalyst for the CuI-catalyzed AAC
reactions.8 We also observed an astounding acceleration
effect by TBTA in the presence of 5 mol % of Cu(OAc)2
without the addition of sodium ascorbate. For the sluggish
reactions involving nonchelating azides, the addition of as
low as 2 mol % of TBTA resulted in complete conversions in
less than 2 h (entries 7-11, Table 3), much faster than what
could be achieved with the assistance of bidentate triazole
additives. The stabilization effect on the CuI oxidation state
and delicately balanced ligand exchange properties of TBTA
have been cited as the source of acceleration in the CuI-
catalyzed AAC reactions.8,10,24 Under the Cu(OAc)2-accelerated
conditions, the presence of TBTA may increase the thermo-
dynamic driving force for the reduction of CuII during the
induction period to rapidly produce a highly catalytic CuI
species for the AAC reactions. This consideration leads to the
hypothesis that chelating azides may also accelerate the CuII
reduction step (blue in Figure 1) to afford highly catalytic CuI
species in a similar manner as that of TBTA, in addition to aid
the metallacycle formation step (red step in Figure 1). The
detailed mechanistic studies on the effect of chelation-en-
abling auxiliary ligands on both CuII reduction and metalla-
cycle formation steps in the AAC reactions is currently
underway.
4. Metal Coordination Properties of Polyaza 1,2,3-Triazo-
lyl-Containing Product Molecules. As a corollary of this
work, we note that an immediate utility of most of the
triazole products derived from chelating carbon azides is
metal ion chelation. We and Crowley et al. described earlier
that 2-picolylazide-derived 1,2,3-triazoles (e.g., T19 in
Table 3) chelate CuII via coordination at pyridyl and triazole
N2 nitrogen atoms.13,27 Complexes of other metal ions of
T19 were subsequently reported.28 In this work, the 2:1
(ligand/CuII) complex of T1 was characterized by X-ray
(25) T18 and T19 were chosen because they were generated in very rapid
(<10 min) AAC reactions under Cu(OAc)2-accelerated conditions. T1 was
chosen as a representative from the triazole molecules reported in this work.
(26) There is an exception for 1-azidooctane, which showed no improve-
ments in overall yield in the presence of T18 over 24 h (entry 1, Table 3).
(27) Crowley, J. D.; Bandeen, P. H.; Hanton, L. R. Polyhedron 2010, 29,
70–83.
(28) Urankar, D.; Pinter, B.; Pevec, A.; Rroft, F. D.; Turel, I.; Kosmrlj, J.
Inorg. Chem. 2010, 49, 4820–4829.
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TABLE 3. Effect of Triazole Ligands as Additivesa
aGeneral conditions: azide (0.2 mmol), triazole additive (0.02 mmol), alkyne (0.2-0.22 mmol), t-BuOH (0.5 mL), and Cu(OAc)2 (25 μL, 0.4 M
solution in H2O, 10 μmol). bIsolated yields after column chromatography; values in parentheses represent yields of isolated products in the absence of
triazole additives. cWith 10 mol % of TBTA. dWith 2 mol % of TBTA.
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FIGURE 4. ORTEP (50% ellipsoids) diagrams of (A) [Cu(T1)2(H2O)2]2þ. Selected distances (A): Cu1-N1 2.073, Cu1-N3 1.995, Cu1-O2
2.330. (B) Hydrogen bond-linked, π-π interaction-stabilized interdigitating chain structures found in the solid state (hydrogen atoms are
omitted for clarity).
crystallography (Figure 4A). A Jahn-Teller distorted octa-
hedral CuII center was observed where the two bidentate T1
ligands constitute the equatorial plane. Instead of CH3CN
solvent molecule, perchlorate, or chloride counterions as shown
in the previously two reported analogous structures,13,27 two
water molecules assume the elongated apical positions. The
unique lability of the apical coordination at a CuII center has
been exploited in CuII-based Lewis acid catalytic processes for
rapid binding and activation of eletrophilic substrates and
turnover of product molecules.29,30
Complex [Cu(T1)2(H2O)2](ClO4)2 forms an extended struc-
ture in the solid state via a rich variety of supramolecular forces
(Figure 4B). All of the oxygen atoms are involved in hydrogen
bonding interactions. The complexes align in one-dimensional
chains through the hydrogen bonds between the apical water
ligands (O O = 3.030 A). The interdigitating adjacent
3 3 3
chains are primarily stabilized by the π-π interactions
(∼3.5 A) between electron-rich methoxyphenyl and the elec-
tron-poor CuII-bound triazolyl groups (only a partial complex
in the adjacent chain is shown in Figure 4B). The chains are
further locked in place via the hydrogen bonds between the
water ligands and the methoxyl oxygens. In the absence of the
methoxy groups as in the previously reported CuII complexes
of ligand T19 (Table 3), the one-dimensional polymeric chain
structure was not afforded.13,27 Although the combined use of
metal coordination and hydrogen bonding has been applied in
crystal engineering to afford one-dimensional organometallic
polymers,31,32 it is rare to observe that both hydrogen bond
donors and acceptors originate from the metal centers. The
observed one-dimensional chain structure was by no means
obtained via deliberate design. However, the emerged syner-
gistic effect of metal coordination, bifurcated hydrogen bond-
ing, and π-π interaction may be considered a viable approach
in crystal engineering to afford tightly stacked extended metal-
containing periodic structures.
The triazole product T6 (entry 9 in Table 1) is a tetra-
dentate metal coordination ligand. X-ray crystal structures
FIGURE 5. ORTEP (50% ellipsoids) diagrams of (A) [Zn(T6)(CH3-
CN)]2þ. Selected distances (A):Zn1-N1 2.056, Zn1-N2 2.049, Zn1-N3
2.251, Zn1-N5 2.063, Zn1-N7 2.061. (B) [Cu(T6)(CH3CN)(ClO4)]þ.
Select distances (A): Cu1-N6 1.985, Cu1-N7 2.021, Cu1-O4 2.605,
Cu1-N1 2.222, Cu1-N5 1.976, Cu1-N4 2.048. (C) [Cu(T6)(H2O)-
(ClO4)]þ. Select distances (A): Cu31-N34 2.024; Cu31-N35 1.983;
Cu31-N33 2.270; Cu31-N36 1.992; Cu31-O22 1.962; Cu1-O16
2.742.
of the ZnII and CuII complexes of T6 display coordination
of N2 of the 1,2,3-triazolyl group with metal ions to form
(29) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325–335.
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1405.
six-membered rings (Figure 5), in addition to the binding
from the more conventional dipicolylamino motif. The ZnII
(32) Brammer, L.; Rivas, J. C. M.; Atencio, R.; Fang, S.; Pigge, F. C. J.
Chem. Soc., Dalton Trans. 2000, 3855–3867.
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Kuang et al.
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center adopts a trigonal bipyramidal geometry. In the CuII
structures, Jahn-Teller distorted octahedrons were observed
where the N2 of the triazolyl group and the perchlorate ion are
found at the long apical positions. The unit cell of the CuII
complex contains two chemically distinct species where the CuII
centers bind at equatorial positions with a CH3CN molecule
(Figure 5B) and a water molecule (Figure 5C). As characterized
in a similar compound, the ZnII affinity of this tetradentate
ligand core is in the nanomolar (Kd) range.14 Therefore, T6
represents a new high-affinity ligand motif for transition metal
ions which may be utilized in applications such as metal ion
sensing14 or organometallic catalyst design.33
were recorded at 300 and 75 MHz, respectively. All chemical
shifts were reported in δ units relative to tetramethylsilane. The
syntheses and characterizations of carbon azide substrates 1, 2,
7, 16 and triazole products T2, T7, T16, T18, T19 were reported
previously.8,13,14
General Procedure for the Cu(OAc)2-Accelerated AAC Reac-
tion. Carbon azide (0.20 mmol), t-BuOH (0.5 mL), and
p-ethynylanisole (29 mg, 0.22 mmol) were added to a 2-dram
sample vial followed by the addition of Cu(OAc)2 (25 μL, 0.4 M
solution in H2O, 10 μmol). The vial was capped, and the reaction
mixture was stirred at rt until the reaction was completed as
shown by TLC (CH2Cl2/EtOAc = 10/1). The reaction mixture
was directly loaded onto a short plug of silica gel. After elution
with EtOAc (∼100 mL), the solvent was removed in vacuo and
the isolated product was characterized by 1H NMR, 13C NMR,
and high-resolution mass spectrometry (HRMS). If needed, the
triazole product was further chromatographed using a finer
solvent gradient to afford the analytically pure material.
Synthesis of Azide 3. Unless otherwise stated, this is a
common procedure for the preparation of all azide substrates.
Warning! Low molecular weight carbon azides used in this study
are potentially explosive. Appropriate protection measures should
always be taken when handling these compounds. 1-Benzyl-
2-(chloromethyl)-H-imidazole hydrochloride (244 mg, 1 mmol)
was dissolved in CH3CN (5 mL). N,N-Diisopropylethylamine
(130 mg, 1 mmol), sodium azide (282 mg, 4.3 mmol), 18-crown-6
(catalytic amount), and tetrabutylammonium iodide (catalytic
amount) were added to the reaction vessel sequentially. The
reaction mixture was stirred at rt for 19 h before EtOAc (30 mL)
was added. The white precipitate was filtered off, and the
solution was washed with basic brine (saturated NaCl solution
that is basified using concentrated NaOH to pH 11, 2 ꢀ 40 mL).
The organic portion was dried over anhydrous Na2SO4. The
solvent was evaporated under vacuum to afford compound 3
(170 mg, 80%): 1H NMR (300 MHz, CDCl3) δ (ppm) 7.72 (d,
J = 7.5 Hz, 3H), 7.47 (d, J = 7.9 Hz, 2H), 7.42 (s, 1H), 7.31 (s,
1H), 5.55 (s, 2H), 4.73 (s, 2H); 13C NMR (75 MHz, CDCl3) δ
(ppm) 142.2, 135.6, 128.9, 128.2, 128.1, 126.6, 121.6, 49.7, 46.3.
The preparations of non-arylmethyl azides required longer
reaction time and/or higher temperature.
Procedure for Preparing [Cu2(11)2Cl4]. The methanolic solu-
tions of 11 (50 mg, 0.335 mmol, 0.5 mL) and CuCl2 (anhydrous,
46 mg, 0.343 mmol, 0.5 mL) were combined and mixed well. The
solvent was then removed in vacuo, and the solid product was
rinsed with diethyl ether three times. The product was dried
under vacuum for 10 min before being redissolved in methanol
(2 mL). The solution was passed through a plug of fiberglass
filter paper before being set up for vapor diffusion of diethyl
ether to obtain the single crystals of the copper complex
[Cu2(11)2Cl4] suitable for X-ray crystallographic analysis.
X-ray Crystallography. Crystals were mounted on a nylon
loop by the use of heavy oil. The samples were held at about
-100 °C for data collection. After finding a crystal that indexed
to give a satisfactory unit cell, a full data set was taken at low
temperature on an APEX II using a detector distances of 6 cm.
The number of frames taken was typically 2400 using 0.3° omega
scans with 20 s of frame collection time. Integration was
performed using the program SAINT, which is part of the
Bruker suite of programs. Absorption corrections were made
using SADABS. XPREP was used to obtain an indication of the
space group, and the structure was solved by direct methods and
refined by SHELXTL. The non-hydrogen atoms were refined
anisotropically. The hydrogens were typically constrained as a
riding model, though with rare exceptions, the data were good
enough that hydrogen assignment could be done directly.
The crystal for the T6/Zn(ClO4)2 complex was found to be a
nonmereohedral twin. It was indexed by CELL_NOW, and the
data were integrated by the program SAINT and the scaling
Conclusion
In summary, we have studied the reactivities of a series of
carbon azides capable of chelating with CuII. Azides with
auxiliary nitrogen donor ligands show higher reactivity than
those with oxygen and sulfur donors (with the exceptions of
the two azidocarboxylates in Table 2, entries 1 and 2). The
high reactivities of chelating carbon azides are attributed to
the fact that chelation-assisted binding between the alkylated
azido nitrogen and the catalytic copper center greatly en-
hances the electrophilicity of the azido group, which lowers
the kinetic barrier to form the key metallacycle intermediate
upon nucleophilic attack by the copper acetylide. The bidentate
triazolyl-containing compounds were shown to moderately
accelerate AAC reactions involving unactivated (nonchelating)
azides, suggesting the possibility of autocatalysis in AAC reac-
tions under the CuII-accelerated conditions. The reactions
involving nonchelating azides were dramatically accelerated
by the polytriazole ligand TBTA developed by Fokin et al.
(although the overall rates as represented by the time required
for completion are still slower than those involving chelating
azides such as 1, 2, 4, 6, 7, and 11). This observation leads to the
hypothesis that chelating azides may have similar capacities to
that of TBTA in assisting the reduction of CuII to highly
catalytic CuI species, in addition to enhancing the electrophili-
city of the azido group in the step of metallacycle formation.
Lastly, the utility of triazolyl-containing product molecules
derived from chelating carbon azides as effective polydentate
ligands for transition metal ions such as CuII and ZnII was
demonstrated in two cases by X-ray crystallography. These
observations motivate us to explore further (1) the mechanistic
front of this operationally simple, yet mechanistically complex
reaction, especially the role of copper/carbon azide interactions,
and (2) the functional potential of the triazole molecules derived
from chelating azides as multidentate ligands for transition
metal ions.
Experimental Section
Materials and General Methods. Reagents and solvents were
purchased from various commercial sources and used without
further purification unless otherwise stated. The purity of Cu-
(OAc)2 is over 98þ%. Analytical thin-layer chromatography
(TLC) was performed using TLC plates precoated with silica gel
60 F254. Flash column chromatography was performed using
40-63 μm (230-400 mesh ASTM) silica gel as the stationary
phase. Silica gel was carefully flame-dried under vacuum to
remove absorbed moisture before use. 1H and 13C NMR spectra
(33) Bergbreiter, D. E.; Hamilton, P. N.; Koshti, N. M. J. Am. Chem. Soc.
2007, 129, 10666–10667.
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Kuang et al.
JOCArticle
done by TWINABS. The structure was solved using the hkl4
data set and refined by the hkl5 corrected data set. The main
molecule resolved nicely, giving chemically reasonable bond
distances and ellipsoids. Not surprisingly, the perchlorate coun-
terions are somewhat disordered. The disorder could be refined
using the part commands and a few restraints, but the data in the
.cif file are as in the final refinement before attempting to model
the disorder.
ligand water. The hydrogens in both cases were refined, giving
reasonable distances and angles. As is quite common with these
compounds, the only significant disorder was found around a
couple of the perchlorate ions. Most of the hydrogens atoms
were assigned and refined as riding molecules, but the data were
good enough for all of the hydrogens around the water oxygen
to be resolved.
The T6/Cu(ClO4)2 complex was refined in P2(1)/c and con-
tains two independent and slightly different copper complexes
with four perchlorate counterions. Solvent molecules within the
structure are two CH3CN molecules and one water molecule.
The copper in the complex can be thought of as being a distorted
octahedron with a perchlorate ion and a solvent molecule
occupying cis positions. In one molecule, CH3CN was the
solvent, and in the other, a water molecule occupies the sixth
spot. The solvent water molecule is hydrogen bonded to the
Acknowledgment. This work was supported in part by
NIGMS (R01GM-081382) and NSF (CHE-0809201).
Supporting Information Available: Experimental proce-
dures, characterization of new compounds, and .cif files for
[Cu2(11)2Cl4], [Cu(T1)2(H2O)2](ClO4)2, [Cu(T6)(CH3CN/H2O)-
(ClO4)](ClO4), and [Zn(T6)(CH3CN)](ClO4)2. This material is
available free of charge via the Internet at http://pubs.acs.org.
6548 J. Org. Chem. Vol. 75, No. 19, 2010