Insight into the Mechanism of the CuAAC Reaction by Capturing the Crucial Au4Cu4-π-Alkyne Intermediate

Article abstract of DOI:10.1021/jacs.0c12498

The classic Fokin mechanism of the CuAAC reaction of terminal alkynes using a variety of Cu(I) catalysts is well-known to include alkyne deprotonation involving a bimetallic σ,π-alkynyl intermediate. In this study, we have designed a CNT-supported atomica

Full text of DOI:10.1021/jacs.0c12498

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Insight into the Mechanism of the CuAAC Reaction by Capturing the
Crucial Au4Cu4−π-Alkyne Intermediate
Yaping Fang,# Kang Bao,# Peng Zhang,# Hongting Sheng,* Yapei Yun, Shu-Xian Hu,* Didier Astruc,*
and Manzhou Zhu*
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ABSTRACT: The classic Fokin mechanism of the CuAAC reaction of terminal alkynes using a variety of Cu(I) catalysts is well-
known to include alkyne deprotonation involving a bimetallic σ,π-alkynyl intermediate. In this study, we have designed a CNT-
supported atomically precise nanocluster Au4Cu4 (noted Au4Cu4/CNT) that heterogeneously catalyzes the CuAAC reaction of
terminal alkynes without alkyne deprotonation to a σ,π-alkynyl intermediate. Therefore, three nanocluster−π-alkyne intermediates
[Au4Cu4(π-CHC-p-C6H4R)], R = H, Cl, and CH3, have been captured and characterized by MALDI-MS. This Au4Cu4/CNT
system efficiently catalyzed the CuAAC reaction of terminal alkynes, and internal alkynes also undergo this reaction. DFT results
further confirmed that HCCPh was activated by π-complexation with Au4Cu4, unlike the classic dehydrogenation mechanism
involving the bimetallic σ,π-alkynyl intermediate. On the other hand, a Cu11/CNT catalyst was shown to catalyze the reaction of
terminal alkynes following the classic deprotonation mechanism, and both Au11/CNT and Cu11/CNT catalysts were inactive for the
AAC reaction of internal alkynes under the same conditions, which shows the specificity of Au4Cu4 involving synergy between Cu
and Au in this precise nanocluster. This will offer important guidance for subsequent catalyst design.
he metal-catalyzed azide−alkyne cycloaddition (MAAC)
structural integrity before and after catalysis.25 Therefore, we
selected a carbon-nanotube-(CNT)-supported atomically
precise bimetallic NC, noted in short Au4Cu4/CNT, as the
model catalyst. Interestingly, the capture of several terminal
alkynes in π-complex intermediates was probed as well as the
ability of Au4Cu4/CNT to serve as a heterogeneous CuAAC
catalyst for terminal alkynes under mild conditions. Con-
comitantly, DFT studies have been conducted to examine the
possibility of alkyne activation by π-complexation with Au4Cu4
rather than deprotonation. The CuAAC activity of mono-
metallic Au11/CNT and Cu11/CNT nanocatalysts has also
been compared to that of Au4Cu4/CNT in order to shed light
on the catalytic synergy between Au and Cu in Au4Cu4.
In order to avoid pretreatment damaging the intact
structure, [Au4Cu4(dppm)2(SAdm)5]Br NC (denoted
Au4Cu4) was chosen as the model catalyst, since all the Cu
atoms in Au4Cu4 have been confirmed to be in the oxidation
state I. The Au4Cu4 NC was synthesized and purified
according to the literature26 and characterized by UV−vis,
MALDI-MS, and X-ray photoelectron spectroscopy (XPS)
analyses as shown in Figure S1. Then, the corresponding
Au4Cu4/CNT was prepared and characterized by FT-IR, XRD,
TEM (including element mapping and EDS), and XPS
analyses (Figures S2−S4). To sum up, all the tests indicated
T
for click chemistry, especially solvated CuACC sys-
tems,1−4 is of paramount importance for rapid assembly of
functional molecules1−3 and has been widely applied in the
field of small-molecule syntheses,1−5 polymeric materials,6 and
biochemical systems.7 The well-recognized CuAAC mecha-
nism using a variety of Cu(I) catalysts first involves a Cu−
alkyne π-complex that converts into a Cu2−σ,π-alkynyl
intermediate species.8−10 Consistently, very few Cu catalysts
have been found to catalyze the AAC reaction of internal
alkynes,10 because the key intermediate is only obtained by
deprotonation of terminal alkynes. Only strong σ-donor
ligands on Cu such as N-heterocyclic carbenes avoid alkyne
deprotonation and thus allow CuACC reaction of internal
alkynes,11,12 common with many RuAAC catalysts that
proceed with different regioselectivity and mechanism.13,14
Under the guidance of “green chemistry”, further research
will focus on the design of durable heterogeneous nano-
catalysts for large-scale industrial applications of AAC
chemistry.11−13 So far, various supported CuAAC have been
reported14−20 and reviewed,15,16 although the large majority of
CuAAC catalysts are homogeneous.1−3 Therefore, acquisition
of a molecular-level understanding of a homogeneous as well as
heterogeneous CuAAC mechanism involving both terminal
and internal alkynes will be the prerequisite to develop
superior heterogeneous CuAAC catalytic systems.
Received: December 1, 2020
Published: January 22, 2021
Nanoclusters (NCs) offer the advantage of having a perfectly
monodisperse and atomically precise nature, thereby providing
superior precision and reproducibility to better decipher the
structure/activity relationships at the molecular level.21−24 In
this regard, Scott and co-workers confirmed that a supported
Cu20 NC preserved the inherent characteristics and maintained
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Figure 3. Kohn−Sham MO analysis and qualitative valence-orbital
energy level schemes of Au4Cu4 (CATA) based on SR-ZORA
B3LYP/TZ2P calculations.
1
Figure 1. (A) H NMR spectrum of the in situ reaction; (B and C)
XPS spectra of Au and Cu in Au4Cu4 NC, Au4Cu4/CNT, and
recycled Au4Cu4/CNT.
Figure 4. (A) Proposed reaction mechanism over the Au4Cu4 NC.
(B) Potential energy diagrams of intermediates and transition states of
reaction between PhCCH and PhCH2N3 catalyzed by Au4Cu4 NC.
the yield of each of the catalysts was about 96%. The CNT,
SiO2, and γ-Al2O3 supports were all inert in the AAC reaction.
Therefore, it was the intrinsic properties of the Au4Cu4 NC
that were responsible for the catalytic activity. Table S2 shows
that Au4Cu4/CNT was tolerant to various substrates in the
AAC reaction, and various alkynes reacted smoothly to afford
the corresponding products with 78.6−98.6% yield. From the
Figure 2. (A) FT-IR and (B) 1H NMR spectra of Au4Cu4 NC,
PhCCH, and the Au4Cu4 NC + PhCCH mixture. (C) TLC of
Au4Cu4 NC, Au4Cu4 NC mixed with PhCCH (PA), and
intermediate Au4Cu4*; MALDI-MS of the intermediate Au4Cu4*
and simulation of the corresponding mass spectrum.
1
in situ H NMR spectrum (Figure 1A), no signal of the Sadm
ligand was detected during the reaction, which confirmed that
Au4Cu4 NC was not at all leaching, and even the signal of the
product (1-benzyl-4-phenyl-1H-1,2,3-triazole) was detected at
the later stage of the reaction. The yield of AAC did not
decrease after three cycles (Table S1, entry 7), and the
recycled Au4Cu4/CNT was characterized by XRD and XPS
analysis. The XRD pattern revealed that there was no
significant change before and after the reaction (Figure S2).
The Au 4f7/2 band (Figure 1B) of recycled Au4Cu4/CNT
(84.51 eV) remained unchanged compared to that of the fresh
that the Au4Cu4 NC was successfully fixed on CNT, and its
structure remained intact and evenly dispersed.
Table S1 shows that Au4Cu4/CNT exhibited excellent
activity with a 96.4% conversion and 100% selectivity for the
AAC reaction of PhCH2N3 with PhCCH. Au4Cu4 NC was
also loaded onto various supports such as SiO2 or γ-Al2O3, and
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Au4Cu4/CNT (84.54 eV). However, the Cu 2P3/2 band
(Figure 1C) in the recovered Au4Cu4/CNT (933.48 eV)
exhibits a slight positive shift compared with the fresh Au4Cu4/
CNT (932.98 eV), which was speculated to be due to PhC
CH coordinated to a Cu atom of the Au4Cu4 NC to form a
feedback π* bond, resulting in charge transfer.27
showed that there was no peak at 7.66 ppm (Figure S8),
indicating that the D ending did not fall off during the whole
reaction. All these results fully demonstrate that PhCCH is
activated through π-complexation with Au4Cu4 rather than
deprotonation. The known monometallic NCs
[ A u 1 1 ( P P h 3 ) 8 C l 2 ] C l ( i n s h o r t , A u 1 1
)
a n d
The uniform Au4Cu4 NC was used to study the mechanism,
and it was found that the catalytic process was different from
the dehydrogenation mechanism.8,9 First, the UV−vis spectra
exhibited a blue shift (Figure S5) when PhCCH was added
to Au4Cu4 NC, while the UV−vis spectra of the Au4Cu4 +
PhCH2N3 mixture remained unchanged. A similar blue shift
was detected when PhCCH and PhCH2N3 were added
together. Thus, the first step of the mechanism is activation of
PhCCH by Au4Cu4. Then, the mixed solution (Au4Cu4 +
PhCCH) was characterized. In the FT-IR spectra (Figure
2A), the characteristic absorption peak of 3293 cm−1 for H−
CCPh was observed, indicating that the H atom of PhC
CH had not been removed during the activation process.28
Meanwhile, the characteristic peak of the CC bond was
shifted from 2109 cm−1 to 2104 cm−1, which was probably due
to feedback alkyne π* bond coordination to Cu, so that the
CC bond becomes longer and its vibration frequency lower.
Furthermore, the Cu 2P3/2 data in the recovered Au4Cu4/CNT
also proved the existence of the feedback π* bond. From the
1H NMR spectrum (Figure 2B), the peak of H-CCPh (3.14
ppm) still existed in the Au4Cu4 + PhCCH mixture,
accompanied by a certain displacement. In the meantime, the
ratio of benzene-ring hydrogen (a) to alkynyl hydrogen (b)
remained 2:1, indicating that PhCCH does not lose its
terminal hydrogen. We conjecture that PhCCH is first
coordinated to Au4Cu4 NC with feedback π* bond formation
of a [Au4Cu4-π-(CHCPh)] intermediate (referred to as
Au4Cu4*) rather than deprotonation of PhCCH. The pure
Au4Cu4* point appears below the Au4Cu4 point from the TCL
board (Figure 2C). The MALDI-TOF data of the Au4Cu4*
sample showed two ion peaks located at 2581.28 and 2647.33
Da, respectively. We speculate that the two peaks are the two
fragment peaks due to instability of Au4Cu4* under the high
energy of mass spectrometry ionization. For example, 2581.28
Da (calculation: [Au4Cu4 + HCCPh − Sadm − H]+) was
Au4Cu4* that lost one Sadm ligand and 2647.33 Da
(calculation: [Au4Cu4]+) was Au4Cu4* that lost PhCCH.
The other two alkynes (HCCPh-4-Cl and HCCPh-4-Me)
were selected to coordinate Au4Cu4 in order to further verify
the Au4Cu4* structure, respectively. Similar results were
obtained by MALDI-TOF analysis. For CHCPh-4-Cl and
CHCPh-4-Me, there are two ions peaks located at 2647.33
and 2615.36 Da (calculation: [Au4Cu4 + CHCPh-4-Cl −
Sadm − H]+) as well as 2647.33 Da and 2595.31 (calculation:
[Au4Cu4 + CHCPh-4-Me − Sadm − H]+), respectively. All
these data confirm that there is no dehydrogenation.
[Cu11(TBBT)9(PPh3)6](SbF6)2 (in short, Cu11) were synthe-
sized for comparison,29,30 and the corresponding supported
catalysts Au11/CNT and Cu11/CNT were fabricated using
similar methods (Figure S9). As expected, the catalytic
performance of Au4Cu4/CNT is essentially different from
that of Au11/CNT and Cu11/CNT. The details are as follows:
the Cu11/CNT exhibited a high activity for the AAC reaction
of PhCCH, comparable to that of Au4Cu4/CNT, while it
had no activity for the internal alkynes. The Au11/CNT was
completely inactive for AAC reactions of both terminal and
internal alkynes. Further, we explored the basic-reaction
experiments (Cu11 + PhCCH) and verified activation of
the acidic hydrogen atom of terminal alkynes by Cu11 through
FT-IR and 1H NMR spectra (Figures S10−S12). These results
indicate that the exceptional properties of Au4Cu4/CNT are
due to a specific synergistic effect between Au and Cu.
DFT calculations reveal that the coordination of PhCCH
is plentiful at the side-coordination sites of Au4Cu4, where
PhCCH prefers to bind to the Cu2 atoms with an
adsorption energy of about −0.24 eV (Table S3), and the
relative energies for each isomer of RE1 are shown in Table S4
(Figures S13 and S14). This side-coordination of PhCCH
on Cu promotes a π−d type interaction. As shown in Figure 3,
there are two pairs of orbital interactions between Cu2 and
PhCCH to stabilize the RE1 complex. The first one is the
interaction between the virtual Cu 4p orbital and the π
bonding of PhCCH, leading to ligand to metal π-donation.
The second one is the interaction between occupied Cu2
orbitals and antibonding π* orbitals of PhCCH, forming the
metal-to-ligand π-back-donation. Thus, the net consequence is
simply viewed as a charge-transfer model where the electron
density transfer from PhCCH to Au4Cu4 leads to Cu2
retaining a +I oxidation state with a gain of negative charge
from Au4 due to the difference in electronegativity. The charge
on the PhCCH increased to +0.35 |e| compared to 0.00 |e|
in pure PhCCH (Table S5), which promotes an
unprecedented charge stabilization effect of Au atoms during
the Cu2−π-PhCCH interaction. Activation of PhCCH
itself through electron density donation is evidenced as shown
by the elongation of the CC bond length from 1.226 Å in
PhCCH to 1.268 Å in RE1 (Table S6). In addition, the
bond length of both Cu2−Au3 and Cu2−Au4 extends upon
the PhCCH side-coordinated on Cu2, implying that the
coordination of PhCCH affects the charge distribution of
the Cu2−Au3−Au4 domain.
The presence of charge transfer is crucial to the reaction
channel between PhCCH and PhCH2N3 because decentral-
ization of charge prevents the formation of the C1−Cu2 bond
or the destruction of the C1−H bond. The formation barrier
for double C−N bonds is +0.96 eV (Table S3) with the Au4
atom migrating back to an adjacent Cu2 site. Afterward, Au3
plays a stabilization role via charge transfer from π-bonding to
Au3 along with a change in Cu2−Au3 distance during the
second PhCCH coordination step at the Cu2 site. The
calculated barrier for the step PhCCH + IV → RE1 + 1,4-
disubstituted 1,2,3-triazoles is only +0.22 eV; thus, the
formation of the C−N bond is the rate-determining step.
In order to obtain convincing evidence for the lack of alkyne
deprotonation along the click reaction mechanism, we have
designed related experiments to prove the π bond activation
mechanism rather than deprotonation. First, we explored the
click reaction in which the terminal acetylene was replaced by
the inactive internal alkynes PhCCPh and PhCCCH3,
respectively, and the corresponding products were obtained
successfully in high yields, which is a rarely observed click
reaction over Cu catalysts (Figures S6 and S7). Next, we used
PhCCD instead of PhCCH for a further controlled
1
experiment. The H NMR spectrum of the purified product
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Finally, the 1,4-disubstituted 1,2,3-triazoles is released and the
RE1 is formed again. In the whole path, the flexibility in
vibration of charge on Au support atoms makes the Cu2 retain
an oxidation state of +I, providing ready access to a CuAAC
mechanism.
230601, China; Key Laboratory of Structure and Functional
Regulation of Hybrid Materials (Anhui University), Ministry
of Education, Hefei 230601, China
Kang Bao − Department of Chemistry and Center for Atomic
Engineering of Advanced Materials, Anhui Province Key
Laboratory of Chemistry for Inorganic/Organic Hybrid
Functionalized Materials, Anhui University, Hefei, Anhui
230601, China; Key Laboratory of Structure and Functional
Regulation of Hybrid Materials (Anhui University), Ministry
of Education, Hefei 230601, China
In conclusion, we have designed a Au4Cu4/CNT catalyst to
investigate the mechanism of the AAC reaction. Three
nanocluster−π-alkyne intermediates [Au4Cu4(−CHC-4-
C6H4R)], R = H, Cl, and CH3 were successfully captured for
the first time, and their structure was shown by MALDI-MS.
1
Moreover, the H NMR, UV−vis, FT-IR, and DFT results
Peng Zhang − Department of Physics, University of Science
and Technology Beijing, Beijing 100083, China
further confirmed that the alkynes were activated by π-
complexation forming Au4Cu4* intermediates (real catalyst)
and that the terminal H atom of HCCPh is not stripped
during catalysis. Interestingly, the Au4Cu4/CNT bimetallic
system achieved CuAAC click reaction of internal alkynes. The
corresponding Au11/CNT and Cu11/CNT nanocatalysts were
not active for internal alkynes, showing that the specific
properties of Au4Cu4 are due to Au−Cu synergistic effects.
Therefore, this work provides an alternative proposal for the
CuAAC mechanism involving the Au4Cu4 NC, which will
provide great support for the design of further catalysts.
Yapei Yun − Department of Chemistry and Center for Atomic
Engineering of Advanced Materials, Anhui Province Key
Laboratory of Chemistry for Inorganic/Organic Hybrid
Functionalized Materials, Anhui University, Hefei, Anhui
230601, China; Key Laboratory of Structure and Functional
Regulation of Hybrid Materials (Anhui University), Ministry
of Education, Hefei 230601, China; orcid.org/0000-
0001-8482-0142
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c12498
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c12498.
■
Author Contributions
#Y.F., K.B., and P.Z. contributed equally to this work.
sı
Notes
The authors declare no competing financial interest.
Experimental procedures, computational details, TEM,
UV−vis, 1H NMR, 13C NMR XPS, XRD, IR, and
absorption spectra (PDF)
ACKNOWLEDGMENTS
■
Financial support by the National Natural Science Foundation
of China (21972001, 21871001, 21976014, and U1930402),
Natural Science Foundation of Anhui Province
(2008085MB37), Anhui University, TianHe2-JK Supercom-
puter Center, University of Bordeaux, and CNRS is gratefully
acknowledged.
AUTHOR INFORMATION
Corresponding Authors
■
Hongting Sheng − Department of Chemistry and Center for
Atomic Engineering of Advanced Materials, Anhui Province
Key Laboratory of Chemistry for Inorganic/Organic Hybrid
Functionalized Materials, Anhui University, Hefei, Anhui
230601, China; Key Laboratory of Structure and Functional
Regulation of Hybrid Materials (Anhui University), Ministry
of Education, Hefei 230601, China; orcid.org/0000-
0002-1146-0948; Email: shenght@ahu.edu.cn
Shu-Xian Hu − Department of Physics, University of Science
and Technology Beijing, Beijing 100083, China;
orcid.org/0000-0003-0127-3353; Email: hushuxian@
csrc.ac.cn
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