Highly active dinuclear copper catalysts for homogeneous azide-alkyne cycloadditions

Article abstract of DOI:10.1002/adsc.201200734

The main feature of the herein presented class of molecularly defined catalysts for the copper-catalyzed azide-alkyne cycloaddition reaction is the presence of two copper centres in one catalyst molecule. We report the facile three-step synthesis of two r

Full text of DOI:10.1002/adsc.201200734

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DOI: 10.1002/adsc.201200734
Highly Active Dinuclear Copper Catalysts for Homogeneous
Azide–Alkyne Cycloadditions
Regina Berg,a Johannes Straub,a Ella Schreiner,a Steffen Mader,a
Frank Rominger,a,b and Bernd F. Strauba,*
a
Organisch-Chemisches Institut, Ruprecht-Karls-Universitꢀt Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg,
Germany
Fax : (+49)-6221-54-4205; phone: (+49)-6221-54-6239; e-mail: straub@oci.uni-heidelberg.de
Abteilung fꢁr Kristallstrukturanalyse, Organisch-Chemisches Institut, Ruprecht-Karls-Universitꢀt Heidelberg, Im
b
Neuenheimer Feld 270, 69120 Heidelberg, Germany
Received: August 16, 2012; Published online: November 28, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200734.
Abstract: The main feature of the herein presented
class of molecularly defined catalysts for the
copper-catalyzed azide–alkyne cycloaddition reac-
tion is the presence of two copper centres in one
catalyst molecule. We report the facile three-step
synthesis of two representative bis-NHC-dicopper
complexes as well as their catalytic performance in
the azide–alkyne cycloaddition. A screening with
one of these complexes has proved its wide applica-
bility and excellent performance as homogeneous
catalyst in various organic solvents and with differ-
ent alkyne and azide substrates.
lar method in polymer and materials science,[3] bioor-
ganic chemistry[4] and drug discovery.[5] Very often,
CuAAC reactions are carried out under “click” condi-
tions,[6] traditionally by in situ reduction of copper(II)
sulfate with sodium ascorbate in aqueous solution.[1b]
However, this procedure is naturally limited to water-
tolerant substrates that are inert towards reducing
agents. Further research efforts have focused on di-
rectly applying copper(I) species together with vari-
ous additives. These additives act as ligands which do
not only stabilize the catalytically active copper(I)
ions with regard to oxidation and disproportionation,
but can also help increase the saltsꢂ solubility and en-
hance their catalytic performance.[7] A variety of pre-
catalyst systems for CuAAC reactions is shown in
Figure 1.
Keywords: click chemistry; copper; cycloaddition;
homogeneous catalysis; N-heterocyclic carbenes
Fokin and Finn have found the rate order with re-
spect to the concentration of copper(I) ions to be two
for both ligand-free[13] and most ligand-containing[7b,14]
The copper-catalyzed azide–alkyne cycloaddition for CuAAC reactions, which suggests the participation of
the synthesis of 1,4-disubstituted 1,2,3-triazoles two copper(I) ions in the rate-determining step.[15]
(CuAAC, Scheme 1)[1] is a variant of Huisgenꢂs 1,3-di- This hypothesis is supported by DFT calculations
polar cycloaddition[2] which disburdens the thermal which have predicted the mechanistic route involving
reaction from its major drawbacks such as poor regio- dinuclear copper(I) m-acetylide complexes to be much
selectivity, long reaction times and harsh conditions.
more favourable than a mononuclear pathway.[16]
Due to its broad applicability and straightforward Based on these findings and the isolation of inter-
procedures, the CuAAC reaction has become a popu- mediates,[17] we postulate a consistent mechanism for
CuAAC reactions (Scheme 2).
In contrast to the widely used “black box” reagent
mixtures, our aim was to rationally construct a molecu-
larly defined, highly active catalyst system for homo-
geneous CuAAC reactions. In dependence on the
postulated mechanism, its most important structural
feature is the presence of two copper(I) ions irreversi-
bly bound in the same catalyst molecule in an ade-
quate distance to each other (Figure 2).[18] On the one
Scheme 1. CuAAC reaction of phenylacetylene with benzyl
azide.
hand, this feature entropically favours the coopera-
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Figure 1. Pre-catalyst systems for CuAAC reactions as reported in literature: a) copper(II) sulfate pentahydrate with
sodium ascorbate reducing agent and 1,10-phenanthroline;[7b] b) [Cu(NCCH3)4]PF6 with TBTA;[7a,8] c) copper(I) acetate;[9]
d) [SIPrCuCl];[10] e) [Cu(C186tren)]Br;[11] f) [ICy2Cu]PF6.[12]
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
tion of the two copper(I) centres compared to mono-
nuclear catalysts, which is particularly important with
low catalyst concentrations. On the other hand, the
enthalpically profitable formation of a bridged m-ace-
tylide intermediate is facilitated. It should thus be
possible to effectively catalyze CuAAC reactions in
aprotic solvents under homogeneous conditions with
low catalyst loadings. Moreover, the catalystsꢂ struc-
ture is modular so that its structural components such
as the nature of the NHC ligands, their substituents
and the “sacrificial” labile ligands can be easily
varied.
Although it has long been acknowledged that two
copper(I) ions participate in the CuAACꢂs crucial
mechanistic steps, we are aware of only two referen-
ces to dinuclear copper complexes as pre-catalysts in
this reaction. On the one hand, Finn et al. have realiz-
ed the potential of dinuclear copper(I) complexes.[19]
On the other hand, Williams et al. have explained
Fokinꢂs observation that the rate law of a CuAAC
test reaction in the presence of TBTA is first order
with respect to the concentration of catalytically
active copper(I) ions[14] by crystallizing a dinuclear
TBTA-copper(I) complex.[8]
Scheme 2. Proposed mechanism for the azide–alkyne cyclo-
addition based on DFT calculations;[16] [Cu] stands for a cop-
per(I) complex fragment.
In this context, we present the synthesis of well-de-
fined bis-triazolylidene dicopper(I) complexes corre-
sponding to the structural outline given in Figure 2 as
well as their application in CuAAC test reactions.
The synthesis of complexes 4a/b (Scheme 3) starts
from the corresponding triazoles 1a/b.[20] The intro-
duction of the linker unit proceeds via a double SN2-
reaction with 1,2-dibromoethane in acetic acid. In
order to avoid the presence of halide ions as inhibito-
ry ligands for copper(I),[1c,18] a salt metathesis of
2a/b with hexafluorophosphoric acid yields the bis-
triazolium hexafluorophosphate salts 3a/b. The last
Figure 2. Structural features of target catalyst system and in-
itiation by reaction with alkyne substrate to give the m-ace-
tylide intermediate.
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Highly Active Dinuclear Copper Catalysts for Homogeneous Azide–Alkyne Cycloadditions
Scheme 3. Modular synthesis of catalytically active complexes 4.
step is the reaction with copper(I) acetate and sodium 0.5 mol% for the dinuclear species 4a/b, and
acetate as an additional base in order to deprotonate 1.0 mol% of the mononuclear reference catalyst
the cationic triazolium moieties and form the bis-tria- [ICy2Cu]PF6 in order to have the same net concentra-
zolylidene copper(I) acetate complexes 4a/b, in which tion of copper(I). Even though 4b is less soluble than
the acetate ligand m-coordinates to both copper(I) 4a, a homogeneous stock solution with the desired
centres. The great advantage of triazolylidene ligands concentration of 4b in deuterated dichloromethane
as compared to imidazolylidene or imidazolinylidene was obtained. Upon addition of the catalyst solutions
ligands is the effortlessness with which their precur- 4a/b, [ICy2Cu]PF6 or copper(I) acetate, all reaction
sors, the triazolium salts, can be deprotonated. A base
as weak as sodium acetate is sufficient to produce the
desired complexes under notably mild conditions.
Complexes 4a/b are air-stable as solids for several
days, but are oxidized in solution.
A single crystal X-ray structure of compound 4b is
displayed in Figure 3. However, this image only shows
one monomeric cation of a more complex coordina-
tion polymer. In fact, half the number of copper(I)
ions is not only coordinated via the ligandsꢂ carbene
carbon atoms, but also by the N-2 atoms of proximate
1,2,4-triazolylidenes. Thus, the coordination number
of these copper(I) centres is three and the
À
À
CACHTUNGTRENNUNG(carbene) Cu OACHTUTGNREN(NUGN acetate) angle was found to be
1468. As a consequence of this aggregation, the xylyl-
substituted complex 4b is only slightly soluble in sol-
vents such as tetrahydrofuran or dichloromethane and
quite robust. In contrast, the sterically more encum-
bered mesityl-substituted complex 4a is very well
soluble in all polar aprotic solvents and more sensitive
than its xylyl-substituted analogue 4b, which hints at
a less aggregated structure in the solid state. Complex
4a decomposes in coordinating solvents such as ace-
tone or tetrahydrofuran, but is stable in dichlorome-
thane for several hours. Saturated solutions of 4b in
dichloromethane or tetrahydrofuran are stable for
weeks.
In order to compare the intrinsic catalytic activities
with the help of continuous NMR spectroscopy, cata-
lytic transformations were carried out in the non-in-
terfering solvent deuterated dichloromethane under
Figure 3. ORTEP ellipsoid model of the single crystal X-ray
structure of complex 4b;[21] the hexafluorophosphate coun-
inert gas (Figure 4). The catalyst loading was terion is omitted for clarity.
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Regina Berg et al.
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is significantly slower; after 15 min, only 3% conver-
sion is observed, and only about 60% after 4.5 h. A
comparison with the catalytic activity of copper(I)
acetate is difficult due to its poor solubility. Adding
a saturated solution of copper(I) acetate in dichloro-
methane to the substrate mixture under the same
strictly homogeneous conditions gave poor conver-
sion, indicating that copper(I) acetate is a heterogene-
ous catalyst under the conditions reported in litera-
ture.[9]
According to Figure 4, catalyst 4a is more active at
the beginning of the reaction, but due to its greater
robustness, complex 4b presumably is the overall
more efficient catalyst. Thus, a series of catalytic test
reactions was carried out with 4b using various sol-
vents and substrates. These reactions were monitored
by gas chromatography and are summarized in
Table 1
Figure 4. Reaction of benzyl azide with phenylacetylene in
CD2Cl2 at 238C; dots: 4b (0.5 mol%); triangles: 4a
(0.5 mol%); squares: [ICy2Cu]PF6 (1.0 mol%); grey trian-
gles: CuOAc (homogeneous solution).
These results indicate that catalyst 4b can be used
in a variety of common organic solvents. In general,
non-coordinating solvents such as dichloromethane
mixtures turned slightly yellow before they quickly re- favour the catalytic performance more than coordi-
turned to being colourless. We attribute the yellow nating solvents such as tetrahydrofuran or acetone. In
colour to the formation of transient alkyne or acety- acetonitrile (entry 2), the reaction proceeds compara-
lide copper complexes. During the course of reaction, bly fast, which might be due to the precipitation of
no precipitation was observed, but after several days, the
product,
1-benzyl-4-phenyl-1H-1,2,3-triazole,
the product triazole crystallized. With catalyst 4a, the whereas the reaction mixtures in acetone (entry 3)
reaction reaches 50% conversion within 15 min and is and dichloromethane (entry 4) remain homogeneous
completed within 100 min. The catalytic performance during the whole course of the reaction. Using tetra-
of catalyst 4b is even slightly better with 60% conver- hydrofuran as solvent (entry 1), the reaction mixture
sion after 15 min and full conversion within 65 min. is cloudy during the course of the reaction between
On the other hand, mononuclear catalyst [ICy2Cu]PF6 benzyl azide and phenylacetylene and clarifies when
Table 1. Catalytic transformations with catalyst 4b.
Entry
mol% 4b
R1
R2
Solvent
Reaction time [min][a]
Yield [%][b]
1
2
3
4
5
6
7
8
0.50
0.50
0.50
0.50
0.50
0.50
0.12
0.25
0.37
0.50
0.62
0.74
0.50
0.50
Ph
Ph
Ph
Ph
n-hexyl
CMe2OH
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
CHTol2
CHTol2
THF
270
35
135
45
50
70
105
40
20
15
7
quantitative (n.d.)
quantitative (n.d.)
quantitative (n.d.)
quantitative (96)
quantitative (96)
quantitative (96)
quantitative (n.d.)
quantitative (n.d.)
quantitative (n.d.)
quantitative (98)
quantitative (n.d.)
quantitative (n.d.)
quantitative (98)
quantitative (98)
acetonitrile
acetone
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
9
10
11
12
13
14
5
225
13
CO2Et
[a]
Reaction time (at room temperature, i.e., 26Æ38C) until neither alkyne nor azide could be detected anymore by gas
chromatography.
Yields were determined by gas chromatographic measurements with an internal standard; isolated yields determined
after short column chromatography are given in parentheses.
[b]
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Highly Active Dinuclear Copper Catalysts for Homogeneous Azide–Alkyne Cycloadditions
centrifuged to give a saturated solution of copper(I) acetate
in CD2Cl2.
conversion is completed. Variation of the alkyne sub-
strate shows that the electron-withdrawing ester
group in ethyl propiolate speeds up the transforma-
tion (entry 10), whereas the electron-donating 2-hy-
droxypropan-2-yl group in 2-methylbut-3-yn-2-ol de-
celerates the reaction (entry 6). With the sterically en-
cumbering azide 4,4’-(azidomethylene)bis(methylben-
zene), the catalytic reaction with phenylacetylene is
NMR Experiments
In a J. Young NMR tube, an aliquot of stock solution A
(0.42 mL, 0.42 mmol phenylacetylene, 0.42 mmol benzyl
1
azide) was diluted with CD2Cl2 (0.08 mL). A H NMR spec-
trum was taken to reassess the purity of the substratesꢂ solu-
dramatically slower (entry 13), but not so with ethyl tion. An aliquot of catalyst stock solution B, C, or D
(0.20 mL,
0.002 mmol
catalyst
4a/b,
0.004 mmol
propiolate as reactant (entry 14).
[ICy2Cu]PF6) was added. Likewise, the saturated solution of
copper(I) acetate was added (0.20 mL, concentration un-
known). The samples were brought to the NMR spectrome-
ter immediately after addition of the catalyst (down time:
approximately 3 min). All reactions were continuously
monitored on a Bruker Avance DRX 300 MHz machine at
238C.
In summary, we have presented a highly active
class of catalysts for CuAAC reactions whose main
structural feature is the coordination of two copper(I)
ions by the ancillary ligand system. These dinuclear
complexes are composed of modular components
(NHCs, linker unit, substituents, sacrificial ligands,
counterion), so as to enable the tuning of their char-
acteristics according to specific demands. Further-
more, they are molecularly defined and allow for
strictly homogeneous CuAAC reactions in a variety
of organic solvents. We are currently working on the
isolation and characterization of reaction intermedi-
ates as well as on the synthesis of water-soluble cata-
lysts.
Catalytic Tests with GC Monitoring
Catalyst Stock Solution (i–iv): Complex 4b (14.0 mg,
0.02 mmol) was dissolved in the solvent (4.00 mL; i: THF;
ii: acetonitrile; iii: acetone; iv: DCM) in a Schlenk flask
under inert gas (c4b =0.005 mmolmLÀ1).
Substrate Solution
1 (i–iv): Phenylacetylene (310 mL,
288 mg, 2.82 mmol), benzyl azide (350 mL, 373 mg,
2.80 mmol) and dodecane (350 mL) were dissolved in the
solvent (1.80 mL; i: THF; ii: acetonitrile (use of toluene in-
Experimental Section
stead of dodecane); iii: acetone; iv: DCM) (calkyne =cazide
=
1.00 mmolmLÀ1).
Substrate Solution 2: Ethyl propiolate (284 mL, 275 mg,
2.80 mmol), benzyl azide (350 mL, 373 mg, 2.80 mmol) and
dodecane (350 mL) were dissolved in DCM (1.80 mL)
(calkyne =cazide =1.01 mmolmLÀ1).
Substrate Solution 3: 1-Octyne (410 mL, 308 mg,
2.82 mmol), benzyl azide (350 mL, 373 mg, 2.80 mmol) and
dodecane (350 mL) were dissolved in DCM (1.80 mL)
(calkyne =cazide =1.00 mmolmLÀ1).
Substrate Solution 4: 2-Methylbut-3-yn-2-ol (274 mL,
236 mg, 2.80 mmol), benzyl azide (350 mL, 373 mg,
2.80 mmol) and dodecane (350 mL) were dissolved in DCM
(1.80 mL) (calkyne =cazide =1.01 mmolmLÀ1).
Attention: We strongly advise against the use of catalysts 4
in CuAAC reactions under neat conditions on a gram sub-
strate scale!
Case example: In a three-necked flask equipped with
a hook-up to the Schlenk line for equalization of pressure,
catalyst 4b (40 mg, 0.06 mmol) was kept under inert gas. A
neat mixture of benzyl azide (533 mg, 500 mL, 4.00 mmol)
and phenylacetylene (409 mg, 440 mL, 4.01 mmol) was added
over a septum via syringe while stirring. The thermal excur-
sion of the reaction was observed by a rise in temperature
and a pressure build-up that finally caused the ejection of
the secured stopcock.
Substrate Solution 5: Phenylacetylene (320 mL, 347 mg,
1.46 mmol),
4,4’-(azidomethylene)bis(methylbenzene)
(160 mL, 1.46 mmol) and dodecane (280 mL) were dissolved
Catalytic Tests with Continuous NMR Monitoring
in DCM (700 mL) (calkyne =cazide =1.00 mmolmLÀ1).
Stock Solution A: Phenylacetylene (286 mg, 2.80 mmol),
benzyl azide (373 mg, 2.80 mmol) and 1,4-dioxane (0.08 mL)
Substrate Solution 6: Ethyl propiolate (150 mL, 145 mg,
1.48 mmol),
4,4’-(azidomethylene)bis(methylbenzene)
were dissolved in CD2Cl2 (2.00 mL) (calkyne =cazide
=
(320 mL, 339 mg, 1.43 mmol) and dodecane (250 mL) were
1.0 mmolmLÀ1).
dissolved in DCM (710 mL) (calkyne =1.03 mmolmLÀ1, cazide
=
1.00 mmolmLÀ1).
Stock Solution B: Complex 4a (8 mg, 0.01 mmol) was dis-
solved in CD2Cl2 (1.00 mL) in a Schlenk flask (c4a
=
0.01 mmolmLÀ1).
Exemplary Procedure for 0.5 mol% Catalyst
Concentration
Stock Solution C: Complex 4b (7 mg, 0.01 mmol) was dis-
solved in CD2Cl2 (1.00 mL) in a Schlenk flask (c4b
=
0.01 mmolmLÀ1).
An aliquot of the catalyst stock solution (i–iv, 200 mL,
1.00 mmol) was filled into a GC vial equipped with a magnet-
ic stir bar and diluted with DCM (100 mL) under inert gas.
Stock Solution D: [ICy2Cu]PF6 (14 mg, 0.02 mmol) was
dissolved in CD2Cl2 (1.00 mL) in a Schlenk flask (cNolanꢀs cat.
=
0.02 mmolmLÀ1).
At t=0, the substrate mixture [1ACTHNUGTRNEUNG(i–v)–6, 200 mL, 0.20 mmol]
Saturated Solution of Copper(I) Acetate: Copper(I) ace-
tate (10 mg, 0.08 mmol) was suspended CD2Cl2 (1.00 mL) in
a Schlenk flask and stirred overnight. The suspension was
was added via syringe. The reaction mixture was stirred at
room temperature. In regular intervals, samples (10 mL) of
this reaction mixture were taken over the septum by micro-
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Regina Berg et al.
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liter syringe. These samples were diluted with DCM (5 mL),
filtered over glass Pasteur pipettes filled with cotton and
celite and analyzed by gas chromatography.
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Acknowledgements
Financial support from the German National Academic
Foundation (Studienstiftung des deutschen Volkes) (to R.B.)
and the Ruprecht-Karls-University Heidelberg is gratefully
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