A Fluxional Copper Acetylide Cluster in CuAAC Catalysis

Article abstract of DOI:10.1002/anie.201502368

A molecularly defined copper acetylide cluster with ancillary N-heterocyclic carbene (NHC) ligands was prepared under acidic reaction conditions. This cluster is the first molecular copper acetylide complex that features high activity in copper-catalyzed

Full text of DOI:10.1002/anie.201502368

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201502368
German Edition: DOI: 10.1002/ange.201502368
Click Mechanism
A Fluxional Copper Acetylide Cluster in CuAAC Catalysis**
Ata Makarem, Regina Berg, Frank Rominger, and Bernd F. Straub*
[
13–15]
Abstract: A molecularly defined copper acetylide cluster with
ancillary N-heterocyclic carbene (NHC) ligands was prepared
under acidic reaction conditions. This cluster is the first
molecular copper acetylide complex that features high activity
in copper-catalyzed azide–alkyne cycloadditions (CuAAC)
with added acetic acid even at À58C. Ethyl propiolate
protonates the acetate ligands of the dinuclear precursor
complex to release acetic acid and replaces one out of four
ancillary ligands. Two copper(I) ions are thereby liberated to
most active CuAAC catalysts known to date.
The
isolation of molecularly defined and catalytically active
NHC copper acetylide complexes and clusters from
a copper carboxylate precursor is thus an important goal.
As for the mechanism of the CuAAC reaction, many
experimental results point to the participation of two
copper(I) ions in the rate-determining step (Scheme 1).
form the core of a yellow dicationic C -symmetric hexa-NHC
2
octacopper hexaacetylide cluster. Coalescence phenomena in
low-temperature NMR experiments reveal fluxionality that
leads to the facile interconversion of all of the NHC and
acetylide positions. Kinetic investigations provide insight into
the influence of copper acetylide coordination modes and the
acetic acid on catalytic activity. The interdependence of “click”
activity and copper acetylide aggregation beyond dinuclear
intermediates adds a new dimension of complexity to our
mechanistic understanding of the CuAAC reaction.
A
range of organic transformations with alkyne substrates
are mediated by copper compounds. Reactions featuring
terminal alkynes and copper include Reppeꢀs ethynylation of
[
1]
3
carbonyl compounds,
aminoalkylation, the standard Sonogashira cross-coupling
of terminal alkynes with aryl halides, and oxidative coupling
reactions as developed by Glaser, Hay, Eglinton, and
Cadiot and Chodkiewicz. The research groups of Meldal
and Sharpless discovered the copper-catalyzed azide–alkyne
cycloaddition (CuAAC),
A
coupling reactions for alkyne
Scheme 1. The disfavored mononuclear pathway and favored dinuclear
pathway in the CuAAC click reaction. R, R’=alkyl, aryl, silyl, carbonyl
groups; L=NHC; L’=NHC or solvent; L’’=solvent, acetylide, carbox-
ylate, halide.
[
2]
[
3]
[
4]
[5]
[6]
[
7]
[8,9]
which has emerged as one of the
The postulation of a mononuclear pathway is incompat-
ible with the following experimental results 1) a rate law with
a second-order dependence on the copper(I) concentra-
most important examples of click reactions and has found
broad application in preparative organic chemistry, polymer
science, materials chemistry, and especially in bioconjugation
[
16]
tion, 2) only slow stoichiometric reaction of a mononuclear
NHC copper acetylide complex with an organoazide to form
[
10]
reactions.
Copper acetylides are intermediates for both
[
17]
copper-mediated and copper-catalyzed transformations of
terminal alkynes. The coordination of more than one
copper(I) ion at the acetylide anion drastically increases the
acidity of terminal alkyne substrates by about ten orders of
an eventually isolated triazolide complex, 3) the superior
[13]
catalytic activity of dicopper complexes,
4) the decisive
catalytic role of copper salts added to a mononuclear copper
[
18]
[18]
acetylide, 5) the results of copper isotope studies, and
6) intercepted crucial dicopper intermediates detected by
[
11,12]
magnitude.
Copper(I) complexes with N-heterocyclic
[
19]
carbene ancillary ligands or carboxylate ligands are the
mass spectrometry. Despite these experimental data and
theoretical rationalizations
[
20,21]
in favor of a dinuclear
CuAAC mechanism, pathways with mononuclear copper
acetylide intermediates were still put forward in a recent
theoretical study.
[
+]
[
*] A. Makarem, Dr. R. Berg, Dr. F. Rominger, Prof. Dr. B. F. Straub
Organisch-Chemisches Institut, Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
E-mail: Straub@oci.uni-heidelberg.de
[22]
A stoichiometric CuAAC reaction of benzyl azide with
a tricopper diacetylide complex has been reported, but this
Homepage: http://www.uni-heidelberg.de/fakultaeten/chemgeo/
[
16]
oci/akstraub
reaction did not proceed catalytically. It is thus of central
importance for the understanding of the CuAAC mechanism
as well as for the further development of better-performing
CuAAC catalysts to provide direct experimental data on the
influence of bridging acetylide ligands on the stability and
activity of molecularly defined copper catalysts.
+
[
] Responsible for the single crystal X-Ray diffraction analysis.
[
**] Financial support by the Universität Heidelberg, the DFG, and the
Studienstiftung des deutschen Volkes is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502368.
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Our research group has developed and prepared dinuclear
copper complex 1, which features a bidentate ethylenebis-
1
,2,4-triazol-5-ylidene ancillary ligand. It shows outstanding
catalytic activity in CuAAC reactions in organic solvents such
[13]
as dichloromethane. We herein report the stoichiometric
reaction of this dicopper complex with an excess of the
terminal alkyne ethyl propiolate to yield a yellow solution of
the new octacopper(I) hexaacetylide cluster 2 and a bistria-
zolium salt as precipitate (Scheme 2).
Figure 1. Ball-and-stick models of the dicationic copper(I) acetylide
[24]
cluster 2 in the solid state (CCDC 1042359). Hexafluorophosphate
counterions were omitted for clarity. All hydrogen atoms, six 3,5-xylyl,
and six ethyl groups were removed in the bottom structure fragment.
Colors: C dark gray, H light gray, O red, N blue, Cu orange.
grown from CH Cl /Et O (Figure 1). The C -symmetric
2
2
2
2
Scheme 2. Protonation of the dinuclear CuAAC catalyst complex 1 with
dication comprises three bis-NHC ligands, eight copper(I)
ions, and six acetylide ligands. Nine cuprophilic interactions
with copper–copper distances of 243.7 pm, 245.9 pm,
ethyl propiolate to give cluster 2. E=CO Et, Xyl=3,5-dimethylphenyl.
2
2
61.5 pm, 268.3 pm (each twice), and 264.3 pm thermody-
[
23]
Addition of a large excess of acetic acid to a dichloro-
methane solution of cluster salt 2 leads to reappearance of the
dicopper complex 1, which is stable in this acidic solution for
at least one day.
namically stabilize the cluster.
The two central copper(I) ions are s-coordinated by four
acetylide ligands and each copper center features 18 valence
electrons. The six 16-valence-electron copper–NHC frag-
ments are each coordinated by an acetylide ligand in s-mode
and an acetylide ligand in p-mode (Figure 2, middle struc-
ture). All acetylide ligands coordinate to one copper ion in p-
Apparently, heterolysis of the NHC–copper bond is
readily accomplished via copper acetylide intermediates, but
it cannot be achieved by direct protonation of the NHC–
copper moiety when acetic acid is added to complex 1.
Protonation of an even more basic imidazol-2-ylidene ancil-
lary ligand of a mononuclear copper(I) complex by phenyl-
acetylene has already been described by Díez-Gonzµlez and
[14]
Nolan. To the best of our knowledge, however, protonation
of a copper(I) carboxylate complex by an alkyne to yield free
carboxylic acid and a molecularly defined copper acetylide
has not been reported to date.
Acetylide complex 2 is air-stable in the solid state and air-
stable for at least three days in dichloromethane solution.
Single crystals suitable for X-ray diffraction analysis were
Figure 2. Coordination environments of the eight copper atoms (left
side) and the six acetylide ligands (right side) in cluster 2.
7
432
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mode and to two or three copper ions in s-mode. The
proposed key intermediate in the currently accepted mech-
anistic picture of CuAAC, however, is a dicopper monoace-
tylide that features one s-coordinated and one p-coordinated
copper ion at the acetylide. In this proposed intermediate, the
1
4-valence-electron copper ion binds the organoazide so that
[11]
the first C–N bond can be formed (Scheme 1).
A recurring issue for quantum-chemical calculations in
this field is the presumed binding of aquo ligands at copper
ions with low coordination number in CuAAC model
intermediates, and the proposal of these copper aquo com-
1
[21,22,25]
Figure 4. Temperature-dependent H NMR signal coalescence for clus-
ter 2 (300.13 MHz, CD Cl ).
plexes as catalyst resting states.
Such an approach
2
2
neglects pre-equilibria of presumably unstable copper(I)
aquo acetylide complexes with the actual catalyst resting
state. According to the Cambridge Structural Database, only
one copper(I) acetylide complex with aquo ligands has been
characterized crystallographically in the solid state. Its copper
ions are coordinatively saturated by bridging chloride ligands,
and the aquo ligand is stabilized by the hydroxymethyl
structures depending on subtle changes in the substituents or
solvent environment.
We used ethyl propiolate and benzyl azide in CD Cl at
[27]
2
2
room temperature for a kinetic comparison. Owing to the
highly exothermic nature of the triazole formation, high
dilution of the reaction mixtures is imperative to ensure an
isothermal reaction and to prevent thermal runaway within
minutes. Exclusion of air is mandatory for meaningful kinetic
measurements because of the dioxygen-sensitivity of com-
plex 1 in solution. The concentration of cluster 2 was adjusted
to one third of the concentration of dinuclear complex 1 to
account for the three ancillary ligands in cluster 2. The
catalytic activity of the dicopper complex 1 is significantly
higher than that of cluster 2 (Figure 5).
[
26]
substituent of the acetylide. Future theoretical studies can
rely on coordination modes as found in cluster 2 to search for
catalyst model structures with lower energy.
1
13
1
At room temperature, the H and C{ H} NMR spectra of
cluster 2 only show one set of signals. This provides evidence
for a rapid degenerate rearrangement. The signal of the
anionic terminal carbon of the acetylide at approximately
1
04 ppm coalesces near room temperature, and the internal
acetylide carbon signal at 123 ppm is also broadened
Figure 3).
(
Figure 5. Conversion versus time diagram for the CuAAC reaction of
ethyl propiolate (0.11m) with benzyl azide (0.1m) in CD Cl at 258C,
2
2
1
3
1
catalyzed by 0.9 mol% complex 1 (1.8 mol% Cu) or 0.3 mol% clus-
ter 2 (2.4 mol% Cu).
Figure 3. C{ H} NMR spectrum of cluster 2 (150.93 MHz, 295 K,
CD Cl , 40960 scans).
2
2
Nonetheless, cluster 2 is the first molecularly defined
°
A Gibbs free energy of activation of DGC = (50 Æ
copper acetylide complex that shows catalytic click activ-
À1
[16,28]
3
) kJmol for the interconversion of the three pairs of
ity.
We observed that heterogeneous catalysis with
homotopic xylyl triazolylidene fragments and of the three
pairs of homotopic acetylide ligands can be derived from the
coalescences of six signal groups observed in variable-temper-
17 mol% copper(I) acetate proceeds only slightly faster
than homogeneous catalysis with only one seventh of the
copper amount in the form of cluster 2 (see the Supporting
Information). Cluster 2 is thus significantly more catalytically
active than “free” copper(I). This excludes the possibility that
the catalytic activity of the cluster relies solely or mainly on
the release of free copper(I).
1
ature H NMR spectroscopy (Figure 4). The fluxionality of
cluster 2 is in good agreement with the structural diversity of
copper acetylide aggregates in the solid state observed by
Tasker and co-workers, who have found a variety of cluster
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Addition of acetic acid greatly increases the rate of the
CuAAC reaction of ethyl propiolate and benzyl azide
catalyzed by cluster 2. Under aerobic conditions and in non-
purified solvent at 278C, the yield of triazole product is
essentially quantitative after the few minutes necessary for
the NMR shimming procedure (Scheme 3).
coordinate to three copper ions are candidates for catalyst
resting states in non-acidic CuAAC reaction mixtures. A
better understanding of copper acetylide chemistry will
provide a foundation for the development of even more
efficient CuAAC catalysts and presumably also for the
advancement of copper-mediated transformations of terminal
alkynes in general.
Keywords: catalysis · click chemistry · copper · CuAAC ·
terminal alkynes
How to cite: Angew. Chem. Int. Ed. 2015, 54, 7431–7435
Angew. Chem. 2015, 127, 7539–7543
Scheme 3. Very rapid CuAAC reactions of ethyl propiolate (0.36m) and
benzyl azide (0.36m) with catalyst 2 under aerobic conditions at 278C
and À58C.
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[
2
In summary, we present a missing link between the well-
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tural and spectral properties, and research on CuAAC
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cluster even at À58C imparts a unique significance to their
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Received: February 3, 2015
Revised: March 13, 2015
Published online: April 29, 2015
[
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