Mechanistic study in azide-alkyne cycloaddition (CuAAC) catalyzed by bifunctional trinuclear copper(I) pyrazolate complex: Shift in rate-determining step

Article abstract of DOI:10.1016/j.jcat.2020.07.010

Trinuclear copper(I) pyrazolate [Cu(3,5-(CF₃)₂Pz)]₃ was employed in a mechanistic study of azide-alkyne cycloaddition (CuAAC). It was shown that the copper complex operates as a bifunctional catalytic system (copper source

Full text of DOI:10.1016/j.jcat.2020.07.010

Journal Pre-proofs
Mechanistic Study in Azide-Alkyne Cycloaddition (CuAAC) Catalyzed by
Bifunctional Trinuclear Copper(I) Pyrazolate Complex: Shift in Rate-Deter-
mining Step
Vladimir A. Larionov, Anna R. Stashneva, Aleksei A. Titov, Alexey A.
Lisov, Michael G. Medvedev, Alexander F. Smol'yakov, Andrey M. Tsedili,
Elena S. Shubina, Victor I. Maleev
PII:
S0021-9517(20)30284-0
https://doi.org/10.1016/j.jcat.2020.07.010
YJCAT 13822
DOI:
Reference:
To appear in:
Journal of Catalysis
Received Date:
Revised Date:
Accepted Date:
2 June 2020
13 July 2020
14 July 2020
Please cite this article as: V.A. Larionov, A.R. Stashneva, A.A. Titov, A.A. Lisov, M.G. Medvedev, A.F.
Smol'yakov, A.M. Tsedili, E.S. Shubina, V.I. Maleev, Mechanistic Study in Azide-Alkyne Cycloaddition
(CuAAC) Catalyzed by Bifunctional Trinuclear Copper(I) Pyrazolate Complex: Shift in Rate-Determining Step,
Journal of Catalysis (2020), doi: https://doi.org/10.1016/j.jcat.2020.07.010
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Mechanistic Study in Azide-Alkyne Cycloaddition (CuAAC)
Catalyzed by Bifunctional Trinuclear Copper(I) Pyrazolate
Complex: Shift in Rate-Determining Step
Vladimir A. Larionov,a,b* Anna R. Stashneva,a,c Aleksei A. Titov,a* Alexey A. Lisov,d,e Michael
G. Medvedev,d,e Alexander F. Smol’yakov,a,f Andrey M. Tsedilin,e,† Elena S. Shubina,a Victor I.
Maleeva
aA. N. Nesmeyanov Institute of Organoelement Compounds of Russian Academ y of Sciences,
Vavilov Str. 28, 119991 Moscow, Russian Federation.
bDepartment of Inorganic Chemistry, Peoples’ Friendship University of Russia (RUDN
University), Miklukho-Maklaya Str. 6, 117198 Moscow, Russian Federation
cDmitry Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, 125047
Moscow, Russian Federation
dDepartment of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, 119991
Moscow, Russian Federation
eN. D. Zelinsky Institute of Organic Chemistry of Russian Academy of Sciences, Leninsky
prospect 47, 119991 Moscow, Russian Federation
fPlekhanov Russian University of Economics, Stremyanny per. 36, 117997 Moscow, Russian
Federation
*E-mail: larionov@ineos.ac.ru, tit@ineos.ac.ru
In memory of Professor Rolf Huisgen.
†Present address: Federal State Institution «Federal Research Centre «Fundamentals of
Biotechnology» of the Russian Academy of Sciences», Leninsky prospect 33, build. 2, 119071
Moscow, Russian Federation
Abstract
Trinuclear copper(I) pyrazolate [Cu(3,5-(CF3)2Pz)]3 was employed in a mechanistic study
of azide-alkyne cycloaddition (CuAAC). It was shown that the copper complex operates as a
bifunctional catalytic system (copper source and Brønsted base) under mild conditions (RT and
air atmosphere) at low catalyst loading (1 mol%). The rate-determining step of the reaction is the
first C-N bond formation between azide and acetylene (azide migratory insertion) but not the
copper(I) acetylide formation as commonly assumed. It was supported by the observed kinetic
1

isotope effect equaling 1.1 and by DFT calculations. The reaction has a second-order dependence
on the catalyst concentration implicating the two copper(I) centers participate in the metallacycle
formation step from “bis-butterfly” tetranuclear complex Cu4L4(RC≡CH)2 in the rate-determining
step. DFT calculations proved that the pyrazolate ligand acts as a Brønsted base and deprotonates
the acetylene molecule providing successful catalysis. A plausible catalytic cycle of the reaction
has generated based on DFT calculations.
Keywords:
Click reaction, azide-alkyne cycloaddition, copper(I) pyrazolate, kinetic isotope effect,
DFT calculations, Brønsted base catalysis
1. Introduction
Macrocyclic copper(I) pyrazolates constitute an attractive class of coordination
compounds able to form supramolecular aggregates via metalophilic or acid-base interactions,[1,2]
as well as exhibit bright photoluminescence.[3] However, despite the widespread use of the
copper(I) pyrazolates in coordination and supramolecular chemistry, their potential is still not fully
disclosed. Obviously, such complexes, having the metal ion in the system, can catalyze various
organic transformations. Being the Lewis acids, the copper centers of trinuclear pyrazolate
complexes can activate the substrates via intermolecular acid/base interactions providing the
valuable target products. Meanwhile, the field has great unexplored potential for the catalysis. To
best of our knowledge, only several reports about the application of the trinuclear copper (I) and
(II) pyrazolate complexes as catalysts have been reported so far including our recent work.[4-6] In
2009, Pombeiro et al. have reported the peroxidative oxidation of cycloalkanes catalyzed by the
trinuclear copper(II) pyrazolate derivatives.[4a] The valuable cyclic alcohols and ketones were
isolated with overall yields of up to 34% and TONs up to 42.[4a] In 2017, Li and co-workers have
synthesized multicomponent copper(I) metal-organic frameworks based on 4-pyrazole carboxylic
acid and applied these complexes as catalysts in the oxidation of CO and aromatic alcohols and
the decomposition of hydrogen peroxide (H2O2).[4b] In 2019, Dias and co-workers applied a
copper complex [Cu(3,5-(CF3)2Pz)]3 as a precatalyst for the alkyne C(sp)-H bond carboxylation
with CO2, azide-alkyne cycloaddition reaction and thiol addition to phenylacetylene affording
vinyl sulfides.[6] Also, there are two examples of the application of polynuclear copper complexes
based on pyrazolates as catalysts in literature.[7] For example, Maspero and co-workers have used
the homoleptic tetrameric [Cu(dcsbpz)]4 (dcsbpz = 3,5-dicarbo-sec-butoxy pyrazole) and
[Cu(dtbpz)]4 (dtbpzas = 3,5-di-tert-butyl pyrazole) copper(I) pyrazolate derivatives as catalysts for
the cyclopropanation of alkenes with ethyl diazoacetate with favored formation of the trans-
diastereoisomeric products.[7a] Lang and co-workers have used the polynuclear copper(II)
pyrazolate complex based on 1H-pyrazole-3,5-dicarboxylic acid dimethyl ester as a catalyst in the
2

condensation of nitriles with 2-amino alcohols to produce various 2-oxazolines with up to 90%
yields.[7b] In another work, Martins and Guedes da Silva et al. reported the application of
copper(I) C-scorpionate complexes based on pyrazolates for catalysis of azide-alkyne
o
cycloaddition in an aqueous media, however, a high temperature (125 C) and microwave
irradiation were required in this case.[8]
In 2002, there was a report about the synthesis of alkyne copper complex Cu2(μ-[3,5-
(CF3)2Pz])2(Me3SiC≡CSiMe3)2 as a chemical vapor deposition precursor of copper.[9] Recently,
we and Dias group independently have shown that the acetylenes can coordinate to a trinuclear
copper(I) pyrazolate complex [CuL]3 (L = 3,5-(CF3)2Pz) via π-coordination of a carbon-carbon
triple bond to copper centers forming polynuclear complexes A, B or C correspondingly.[5,6,10]
There was no copper(I) acetylide formation during the interaction in contrast to literature
reports[11] as was proved by NMR-, IR-spectroscopy investigations, and by a single crystal X-
Ray analysis (Figure 1).[5,6]
A
Complex
F3C
CF3
CF3
F3C
R
H
N
N
N
N
CuI
CuII
CuI
N
N
N
N
H
R
F3C
CF3
CF3
F3C
R = Ph
R = hexyl
Our work5
C
Complex
B
Complex
H
H
R2
R1
CF3
CuI
F3C
CuI
F3C
CF3
R1
CuI
R2
CuI
N
N
N
N
N
N
F3C
CF3
N
N
N
N
N
N
F3C
CuI
CF3
CuI
F3C
CF3
CF3
F3C
R1 = R2 = H;
R1 = R2= Et;
H
H
R1 = Ph, R2 = H
Dias work6
Figure 1. Chemical structures of the copper pyrazolate adducts with terminal alkynes.
3

Despite the importance of copper in chemistry and the availability of a wide scope of
copper(I) pyrazolates,[1-3] their use as catalysts in alkyne transformations remain virtually
unexplored. As proof-of-principle, we quite recently demonstrated that the trinuclear copper(I)
pyrazolate complex [CuL]3 efficiently catalyzes the alkyne-azide cycloaddition (CuAAC) (“Click
reaction”)[12,13] of phenylacetylene and 1-octyne with ortho-fluorobenzyl azide (Scheme 1).[5]
[CuL]3
(1 mol%)
N
N
N
+
N3-R'
R
R'
R
1,4 - substituted
CF3
F3C
N
N
Cu
Cu
N
F3C
CF3
N
Cu
N
N
CF3
precatalyst
F3C
[CuL]
3
Scheme 1. 1,2,3-triazole syntheses via “click reaction”.
As known, the resulting 1,4-substituted 1,2,3-triazoles have a broad interest in modern
pharmaceuticals.[14,15] Moreover, CuAAC is a simple and powerful tool to conjugate molecular
pieces together, for instance, in applications of bioconjugation,[15e] surface modification,[16] and
syntheses of new polymeric materials,[17] for construction and modification of MOFs[18], and
etc. To date, a lot of copper(I) catalysts were applied for the CuAAC,[11-13] however, in many
cases, the harsh conditions (polar solvents, high temperatures, extra base, and etc.) are
required.[13d,13g,19,20] Although the mechanism of this reaction is well-known and
studied,[13g,13h,19,20] there is still going disputation about the mechanistic aspect depending on
the catalytic system and substrate class. Commonly, based on works by Finn and Fokin,[13d] and
Zhu,[13g,20d] acetylide formation is the rate-determining step (RDS) of the CuAAC reaction. On
another hand, recently, Seath et al. observed the shift of RDS from acetylide formation to azide
ligation/migratory insertion depending on the structure of substrates.[21]
With these precedents in hand, we aimed to partially fill this knowledge gap. Herein, we
report the detailed mechanistic study of CuAAC reaction catalyzed by the trinuclear copper(I)
pyrazolate complex [CuL]3 (Scheme 1). Experimentally with theoretical insights (DFT
calculations), it was shown that the copper(I) complex operates as a bifunctional catalytic system
(Scheme 1). Moreover, the rate-determining step is the first C-N bond formation between azide
and acetylene (azide migratory insertion) in contrast to the commonly assumed copper(I) acetylide
formation.[13d,20b,20d] Our finding nicely complements the recent observation by Burley and
Watson where an alkyne-specific shift in an RDS was evidenced.[21]
4

2. Results and discussion
The study was started by the investigating of the azide-alkyne cycloaddition reaction of
ortho-fluorobenzyl azide 1a with phenylacetylene 2 catalyzed by the trinuclear copper(I)
pyrazolate [CuL]3 (Table 1). The click reaction conducted in CH2Cl2 in the presence of 1 mol%
copper complex at room temperature under air after 4 hours furnished 1,4-substituted 1,2,3-triazole
3a in >99% conversion (Table 1, entry 1). Importantly, in each experiment no formation of any
side products, even Glaser coupling products,[22] was observed. Next, the solvent effect was
studied (Table 1, entries 2-8).
Table 1. Reaction conditions screening for CuAAC.a
N3
1 mol%
[CuL]3
F
N
N
N
+
CH2Cl2
RT
F
Ph
1a
2
3a
"standard conditions"
change from the
“standard conditions”
None
hexane as the solvent
toluene as the solvent
1,2-dichloroethane as the solvent
MeCN as the solvent
THF as the solvent
MeOH as the solvent
water as the solvent
no solvent
convn
(%)b
entry
time (h)
1
2
3
4
5
6
7
8
9
10
4
4
4
4
4
4
4
4
4
>99
89
76
99
96
68
21
94
>99
NR
3 mol% of CuI instead of [CuL]3 24
3 mol% of CuI and 3 mol% of
24
11
NR
3,5-(CF3)2Pz instead of [CuL]3
3 mol% [Cu(MeCN)4]BF4 instead
of [CuL]3
12
24
traces
aReaction conditions: ortho-fluorobenzyl azide 1a (0.35 mmol),
phenylacetylene 2 (0.35 mmol, 1 equiv.) and [CuL]3 (1 mol%, 3.5 µmol) were
stirred in CH2Cl2 (1 mL) (or another solvent) at room temperature under air at
indicated
time.
bDetermined
by
1H
NMR.
L
=
3,5-
bis(trifluoromethyl)pyrazolate. NR = no reaction.
The conversions in aprotic non-polar organic solvents such as hexane and toluene were slightly
decreased (89% and 76%, correspondingly) (Table 1, entries 2,3). More polar aprotic solvents 1,2-
dichloroethane and MeCN gave excellent conversions after 4 h (Table 1, entries 4,5). The
conversion was lower in THF (67%) (Table 1, entry 6). Expectedly, the protic solvent MeOH was
a too polar reaction media with low conversion (21%) (Table 1, entry 7). Water was also a good
5

tolerant solvent giving the desired product with 94% conversion (Table 1, entry 8). The reaction
conducted in neat ortho-fluorobenzyl azide 1a and phenylacetylene 2 without any solvent also
gave the 1,4-substituted 1,2,3-triazole 3a in >99% conversion (Table 1, entry 9).
Furthermore, the control experiments showed that no target product 3a was formed when
either 3 mol% of CuI or a combination of 3 mol% CuI and 3,5-bis(trifluoromethyl)pyrazole were
used as catalysts (Table 1, entries 10,11). [Cu(MeCN)4]BF4 (3 mol %) gave only a trace amount
of the desired product 3a under optimized conditions (Table 1, entry 12).
2.1 Mechanistic study
Next, we performed a set of experiments, kinetic studies, and measurements for the
mechanistic investigation of the azide-alkyne cycloaddition reaction catalyzed by [CuL]3 with the
involvement of DFT calculations.
As was already mentioned above, we evidenced the direct interaction of copper(I)
pyrazolate with the triple bond of phenylacetylene 2 via η2-coordination and no copper(I) acetylide
complex formation by NMR and IR spectroscopies in our previous work.[5] Furthermore, there
were no any feasible interactions of azide with a complex [CuL]3 in CH2Cl2.[5]
To determine what type of copper-pyrazolate particles are in the solution, the system was
investigated at a molecular level by using electrospray ionization mass spectrometry (ESI-MS).
Mass spectrum of the copper(I) complex [CuL]3 measured in MeCN in a negative mode at
concentration 10-4 mg/mL clearly showed the presence of several metal complex species: [CuL2]–
at m/z 468.9405, [Cu2L3]– at m/z 734.8749, [Cu3L4]– at m/z 1002.8086 and [Cu5Pz6]– at m/z
1534.6836 (see Fig. S1, S3 in SI). On the other hand, the mass spectrum of copper(I) complex
measured in MeCN in a positive mode showed the presence of [Cu2L(MeCN)2]+ at m/z 410.9158
and [Cu3L2(MeCN)2]+at m/z 678.8485 (see Fig. S2, S3 in SI). Unfortunately, we didn’t detect any
alkyne bounded metal complex species in solution when we conducted the experiments with the
addition of phenylacetylene 2 to the solution of [CuL]3 in MeCN. Probably, the reason is the weak
interaction between copper species and alkyne 2 that was not enough stable under ESI-MS
conditions. The addition of 1 equiv. of azide 1d didn’t affect the ratio of the copper ions confirming
there is no interaction between azide and the copper complex [CuL]3 in solution. Notably, the
oxidation of detected [Cu3L4]– ion at m/z 1002.8086 in the presence of oxygen and following by
the coordination with phenylacetylene 2 gave the complex A [5] (the central copper ion has +2
charge in Fig. 1). From another hand, recently Dias and co-workers described the crystal structure
of the di-nuclear complex B (Cu2(μ-[3,5-(CF3)2Pz])2(HC≡CPh)2) (see Fig. 1),[6] which are formed
either after dissociation of [CuL]3 in solution in the presence of alkyne or after the reorganization
of the copper complex A.
6

To ascertain the number of the catalyst molecules in the transition state of the reaction, the
order with respect to the substrates and catalyst had to be quantified. For this purpose, the reactions
were carried out at different concentrations of each substrate/component whilst keeping the other
component concentration constant and monitored by IR spectroscopy. The initial zero order rates
of the reactions were determined and the coefficients x and y in equation 1 were found to be 1.16
and 0.54 respectively (see Fig. S5 and S7 in SI). Thus, ortho-fluorobenzyl azide 1a shows a first-
order behavior that means one molecule of the substrate entered the rate limiting stage of the
reaction (see Fig. S5 in SI). Phenylacetylene 2, in excess amounts, has fractional order (0.54),
suggesting that two molecules of alkyne participate in the transition state and only one of them
reacts (see Fig. S7 in SI) (see also DFT calculations, vide infra). The reaction is second-order in
copper pyrazolate [CuL]3 (z = 1.9) when it is maintained at catalytic levels (<5 mol %, Figure 2).
A second-order dependence on copper is consistent with the commonly accepted kinetic model,
which favors the participation of two copper(I) centers in the metallacycle formation step based
on both kinetic data[13d,20b] and computations.[23] Furthermore, our experimental data have
been proved by DFT calculations (see vide infra).
3a
[ ]
x
y
z
(eq 1)
V =
1a [CuL]
= k [ ] [ ] [ ]
3
2
3a
dt [ ]0
Figure 2. Plot of logV versus log[[CuL]3] for CuAAC of ortho-fluorobenzyl azide 1a and
phenylacetylene 2 in CH2Cl2. Reaction conditions: azide 1a (0.352 mmol), phenylacetylene 2
(0.352 mmol), catalyst [CuL]3 (0.5, 1, 2 and 4 mol%), CH2Cl2 (1.0 mL).
The kinetic significance of alkyne deprotonation revealed was further investigated to
ascertain the rate-determining step (RDS) of the reaction using deuterium KIE experiments. A
7

primary deuterium KIE (kH/kD) of 1.1 was observed in the reaction in CH2Cl2 (see Fig. S9 in SI).
This result is opposite to the commonly assumed mechanism,[13d,20b,20d] where the acetylide
formation is RDS and, on another hand, supports the recent observation by Seath et al.,[21] where
the RDS shifted to azide ligation/migratory insertion step. Next, we performed additional
experiments using MeOH and MeOD as additives and involving phenylacetylenes 2-H and 2-D
(deuterated). The reactions conducted in the presence of 20 equiv. MeOD gave the desired product
3a only with a 5% conversion after 4 hours (Scheme 2a). In contrast, MeOH added lead to the
formation of 3a at 43% and 55% conversions, correspondingly (Scheme 2a). The reaction of
phenylacetylene 2-H with MeOD added gave the desired triazole 3a-D in a 59% yield where 80%
of deuterium was incorporated. A similar experiment with alkyne 2-D in MeOH furnished the
protonated triazole 3a-H (95% proton incorporation) in a 96% yield (Scheme 2b). So, both
experiments proved that the deprotonation of acetylene are occurred by forming the acetylide
complex and, finally, the protonation of the triazole metallocycle by either with acetylene 2 or
methanol has released the catalyst back to the catalytic cycle. Moreover, the presented experiments
clearly show that the presence of protonating agents (MeOH or MeOD) in the reaction mixture
makes difficult the deprotonation step by [CuL]3 shifting the equilibrium of deprotonated
acetylene to it protonated form (see Scheme 2).
a)
N3
1 mol%
F
N
[CuL]3
N
N
R
+
F
Ph
CH2Cl2
4h, RT
2-H
2-D
, R = H
, R = D
1a
3a
alkyne additive (20 equiv.) convn, %
2-H
2-D
2-H
2-D
MeOH
MeOH
MeOD
MeOD
43
55
5
5
b)
1 mol%
[CuL]3
F
N
N
N
H
CH2Cl2
20 eq. CH3OD
18h, RT
Ph
D
80%
N3
2-H
3a-D
+
conv. 59%
N
F
1 mol%
[CuL]3
1a
F
N
N
D
Ph
CH2Cl2
20 eq. CH3OH
18h, RT
H
95%
2-D
3a-H
conv. 96%
Scheme 2. Mechanistic investigations using phenylacetylenes 2-H and 2-D.
8

2.2 DFT calculations
To dissect the reaction mechanism, we have modeled the most likely routes of CuAAC
reaction. The second order in the catalyst [CuL]3 suggests the participation of two copper(I)
centers in the metallacycle formation step. For this purpose, we conducted a computational study
to find the structure of the active catalytic particle.
Based on DFT calculations, we have found that the catalytically active particle is “bis-
butterfly” tetranuclear complex Cu4L4(RC≡CH)2 (bb-S, Fig. 3) which is formed from two
molecules of its resting state – a binuclear “butterfly” B.[24] The complex B was previously
isolated and characterized by a single crystal X-Ray analysis by Parasar et al.[6] Free energy of
tetramer complex bb-S is lower than that of dimer B by 6.2 kcal/mol at experimental conditions.
Complex B itself was also considered a catalytic particle but then the reaction has a very high
energy barrier: 37.1 kcal/mol vs. 21.3 kcal/mol in case of bb-S (see Fig. 3 and S12 in SI). Complex
bb-S as well as its “tetrahedral” counterpart (th-S) were isolated in previous studies.[6,10b] While
th-S is 1.8 kcal/mol lower than bb-S, it also has much more sterically crowded copper atoms, so
only bb-S appears to be able to attach an azide molecule. Thus, the catalytically active particle is
bb-S, which exists in equilibrium with the catalytically inert B and th-S.
In our previous study, we have shown that also a ‘spiro’ complex A (in Figure 1) is
catalytically active in this reaction.[5] This suggests that the complex can reorganize in the reaction
mixture into the catalytic particle B, accompanied by Cu(II)Pz2 precipitation. In this regard, it was
observed by ESI-MS that the copper pyrazolate [CuL]3 can easily dissociate on different particles
in solution (see Figures S1-S3 in SI).
Azide molecule attachment initiates Cu-Pz bond cleavage, during which leaving Pz ligand
acts as a proton acceptor (Brønsted base), leading to the formation of the IM2 complex. Proton
transfer accompanying the azide-induced Cu-Pz bond cleavage has remarkably low activation
energy (16.5 kcal/mol relative to bb-S), which explains the absence of H/D KIE in this reaction.
This also explains the observed reaction inhibition by methanol (see Scheme 2), which likely
protonates the pyrazole ligand after the bond cleavage preventing acetylene deprotonation.
Next, structure IM2 undergoes cycloaddition to form a six-membered cycle (IM3). This
transition state has relative energy of 21.3 kcal/mol, which makes it the rate limiting step of the
studied reaction, as was proposed and proved by Seath et al.[21] At the next stage the second C-N
bond forms via a 13.0 kcal/mol transition state, resulting in a five-membered triazole cycle (IM4).
After that, the proton initially transferred to the Pz ligand returns to the carbon (IM5), product P
exchanges for a new acetylene molecule and the catalytic particle is ready for the next cycle. The
whole catalytic cycle and computed free energies along it are depicted in Fig. 3 (atomic coordinates
and total energies are available in SI).
9

Figure 3. The catalytic cycle, its energetic diagram and some structures of stationary points along
the reaction path. Energies of TS1 and TS2 relative to bb-S are shown on the diagram. All energy
values are in kcal/mol, bond lengths are in Å.
Thus, the main mechanistic feature revealed by calculations is that the main catalytic
particle is a “bis-butterfly” tetranuclear copper complex. Notably, while three pyrazolate
molecules play roles of bidentate ligands that hold copper atoms side by side, the fourth pyrazolate
molecule acts simultaneously as a monodentate ligand and as a Brønsted base deprotonating
acetylene molecule. The computational results fully support the experimental data and confirm the
10

shift of the RDS from acetylide formation to azide ligation/migratory insertion. It was also proved
that the reaction has a second-order dependence on the catalyst concentration where the two
copper(I) centers participate in the metallacycle formation step from the “bis-butterfly”
tetranuclear complex Cu4L4(RC≡CH)2 formed from a complex [CuL]3 in the rate-determining
step.[24]
2.3 Substrate scope
Next, with optimized conditions in hand, we have evaluated the scope and generality of the
reaction with regard to variations of the azides and alkynes (Fig. 4). In all cases, the reaction
practically doesn’t depend on the electron effect of substituents furnishing 1,4-substituted triazoles
3a-j (Fig. 4). The conversions are shown for all products because there is no formation of side
products observed in the reaction.
11

[CuL]3
(1 mol%)
N
N
N
N3-R1
R1
+
R
CH2Cl2
RT
R
1
2
, R = Ph or
1
3
5
or
1
4
, R = C6H13
N
N
N
N
N
R1
N
R1
Ph
5
Ph
5
4
2
3a-i
5a-i
R1
N3
R2
2
5a
5b
5c
5d
5e
: >99% (4 h)
: 80% (18 h)
: 82% (18 h)
: 92% (18 h)
: >99% (4 h)
: >99% (4 h)
1a
1b
1c
1d
1e
3a
: R = 2-F
: >99% (4 h)
: 97% (24 h)
: >99% (14 h)
2
3b
3c
: R = 3-Br
2
: R = 4-Br
2
3d
: R = 2,6-Cl2
: 98% (10 h)
: >99% (4 h)
: >99% (10 h)
2
3e
: R = H
2
1f
3f
: R = 4-tBu
5f
2
1g
1h
3g
3h
: R = 4-CF3
: >99% (4 h)
: >99% (4 h)
5g
5h
: >99% (4 h)
: >99% (4 h)
: 98% (7 h)
2
: R = 4-CN
2
1i
3i
: R = 4-COOMe
: 46% (24 h)
3j
: >99% (4 h)
5i
O
N3
O
Br
1j
5j
: 94% (4 h)
Ph
Ph
Ni
O
O
N
N
O
O
Ni
N
N
N
N
N
N
O
O
N
Ph
Ph
R2
2
6
1a
from : R = 2-F,
7a
: 91% (24 h)
7b
: >99% (24 h)
1j
from
Figure 4. Substrate scope (for all products the conversions are given).
The click reactions of octyne-1 4 with the same set of azides 1a-j (Figure 4) were also
successfully carried out. For most of the azides 5a-j, apart from a few exceptions (products 5b-d),
comparable results were observed in terms of yields (80–>99%) as for phenylacetylene 2.
Finally, to further emphasize the applicability and to demonstrate the practicability of the
developed catalyst, we performed the reactions with a chiral Ni(II) complex 6 bearing an acetylene
fragment in the side chain and azides 1a,j. As we recently demonstrated,[25] the side chain
modification of a chiral Ni(II) complex 6 via “click chemistry” leads to the amino acids with 1,2,3-
triazole appendage that are interesting biologically active candidates.[15f,15h] However, the harsh
o
conditions (DMSO, Et3N and 70 C) in our previous work, in some cases, furnished the desired
12

products in low yields.[25] Herein, the cycloaddition of the Ni(II) complex 6 with azides 1a or 1j
in the presence of only 1 mol% catalyst [CuL]3 under mild conditions (RT, CH2Cl2) gave the
desired products 7a and 7b in a 91% and >99% conversions vs previous our results (71% and 76%
yields, correspondingly).[25] The obtained chiral Ni(II) complexes 7a and 7b after acidic
decomposition give the corresponding valuable enantiopure 1,2,3-triazole containing (α)-amino
acids.[25]
3. Conclusions
In summary, we have demonstrated that the trinuclear copper(I) pyrazolate complex
[CuL]3 efficiently catalyzed an azide-alkyne cycloaddition reaction under relatively mild
conditions. By experimental data and DFT calculations, we proved that the pyrazolate ligand in
the copper complex acts as a Brønsted base and deprotonates the acetylene molecule for the
successful reaction. The rate-determining step of the reaction is the first C-N bond formation
between azide and acetylene (azide migratory insertion), as supported by DFT calculations. The
reaction has second-order on copper suggesting that the two copper(I) centers participate in the
metallacycle formation step. The connotation of the results is that the rate-determining step of
CuAAC reactions can shift depending on the catalytic system and substrate class. This
phenomenon was underestimated enough previously. Our finding nicely complements the recent
observation by Seath et al.[21] where an alkyne-specific shift in a rate-determining step was
evidenced depending on the structure of substrates. Furthermore, the developed method was
applied for the synthesis of the scope of valuable 1,4-substituted 1,2,3-triazoles and amino acid
derivatives bearing the triazole motif in high yields. The copper complex is robust, simple to
prepare, and catalyzes the reaction even in water or without solvent (neat conditions). This work
paves the way for the study of the CuAAC reaction mechanism and the design of new catalytic
systems based on copper complexes.
4. Experimental section
4.1. General information
All solvents purchased from commercial suppliers were used without further purification (CH2Cl2,
CD2Cl2, hexane, 1,2-dichloroethane, MeCN, MeOH). Solvents were distilled under an atmosphere
of argon from sodium (THF, toluene). Purchased phenylacetylene (2) and 1-octyne (4) from
commercial suppliers were used without further purification. The trinuclear copper(I) bis-
(trifluoromethyl)pyrazolate ([CuL]3) was prepared according to a published procedure.[26]
Azides (1) was synthesized according to a literature procedure.[27] A chiral Ni(II) complex 6 was
13

available from our previous work.[25] If not stated otherwise, flash column chromatography was
performed with silica gel 60 M from Macherey-Nagel.
4.2 Instrumentation
Proton nuclear magnetic resonance (1H-NMR) spectra and carbon nuclear magnetic resonance
(13C-NMR) spectra were recorded on a Bruker Avance 400 spectrometer operating at 400 MHz
(1H) and 101 MHz (13C{1H}). Chemical shifts are reported in ppm relative to the residual solvent
1
13
peak (CDCl3: δ = 7.26 ppm for H-NMR, δ = 77.2 for C-NMR). NMR data are reported as
follows: chemical shift, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m
= multiplet), coupling constant, integration, and nucleus. IR spectra were recorded on FT-IR
Spectrometer Nicolet 6700 using CaF2 cuvettes.
High-resolution mass spectra were registered on Bruker maXis QTOF instrument equipped with
electrospray ionization (ESI) ion source. The measurements were performed in positive (HV
capillary at 4.5 kV, spray shield offset at -0.5 kV) and negative (HV capillary at -4.0 kV, spray
shield offset at -0.5 kV) modes with a scan range of m/z 50−2000. External calibration was
performed using a low concentration tuning mix solution (Agilent Technologies). Direct syringe
injection was used for all analyzed solutions in MeCN at a flow rate of 5 μL/min. Nitrogen was
used as both nebulizer gas at 1 bar and dry gas at 4.0 L/min, 200 °C. All recorded spectra were
processed using Bruker Data Analysis 4.0 software package.
4.3 DFT calculations
All calculations were performed at PBE0[28]-D3BJ[29]/def2-SVP[30]/PCM[31](CH2Cl2) level of
theory in Gaussian16 program package.[32] PBE0 functional was selected as widely reliable and
physically grounded.[33] The solvent effects of CH2Cl2 were implicitly accounted with the
polarizable continuum model. Free energies were calculated with Head-Gordon[34] and
Grimme[35] quasi-harmonic corrections implemented in GoodVibes 3.0.[36]
4.4 General procedure for the click reaction between azides 1 and phenylacetylene 2 or 1-octyne
(4) catalyzed by complex [CuL]3
To a solution of complex [CuL]3 (1 mol%, 2.8 mg, 3.55 10-3 mmol) and acetylene 2 or 4 (0.352
mmol) in CH2Cl2 (1 mL) in a vial was added azide (1) (0.352 mmol) under air. The vial was then
tightly capped with a rubber-sealed screw cap and the mixture was stirred at room temperature for
24 h. Afterward, the mixture was concentrated under reduced pressure. The residue was purified
by flash chromatography on silica gel (CH2Cl2) to afford the triazoles 3 or 5 as white powders.
14

The formation of products was confirmed by comparing the 1H NMR data with literature reports
(see in SI).
4.5 General procedure for the click reaction between azides 1 and Ni(II) complex 6 catalyzed by
complex [CuL]3
To a solution of complex [CuL]3 (0.79 mg, 1 mol%, 1.0 10-3 mmol) and 6 (75 mg, 0.1 mmol) in
CH2Cl2 (0.3 mL) in a vial was added azide 1a or 1j (0.12 mmol) under air. The vial was then
tightly capped with a rubber-sealed screw cap and the mixture was stirred at room temperature for
24 h. Afterward, the mixture was concentrated under reduced pressure. The residue was purified
by flash chromatography on silica gel (eluent: CH2Cl2/acetone (5:1)) to afford the Ni(II) complex
with triazole appendage 9a or 9b as a red powder. The formation of products was confirmed by
comparing the 1H NMR data with literature reports (see in SI).
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
Author Contributions
V.A.L. directed the research. V.A.L and A.A.T. designed the experiments. A.R.S. carried out the
majority of the synthetic experiments. V.A.L and A.A.T. performed kinetic experiments. A.A.L
and M.G.M. performed the DFT calculations. A.M.T. performed the HRMS measurements.
V.A.L, A.A.T., A.A.L., M.G.M., A.F.S., E.S.S. and V.I.M. performed data processing and
analysis. V.A.L., A.A.T. and A.A.L. wrote the manuscript with feedback given by all contributors.
Acknowledgements
The substrate scope investigation was supported by the Russian Foundation for Basic
Research (RFBR grant no. 18-33-20003). The publication has been prepared with the support of
the RUDN University Program 5-100 (the kinetic investigations). The IR spectroscopy
investigations of the [CuL]3 interactions with alkynes were performed as a part of the project
RFBR 18-33-20060. Quantum chemical calculations were supported by the Russian Foundation
for Basic Research (RFBR grant no. 19-33-60073). NMR measurements were performed with
financial support from the Ministry of Science and Higher Education of the Russian Federation.
The Siberian Branch of the Russian Academy of Sciences (SB RAS) Siberian Supercomputer
Center is gratefully acknowledged for providing supercomputer facilities. This work has been
carried out using computing resources of the federal collective usage center Complex for
15

Simulation and Data Processing for Mega-science Facilities at NRC “Kurchatov Institute”,
http://ckp.nrcki.ru/. The research is carried out using the equipment of the shared research facilities
of HPC computing resources at Lomonosov Moscow State University.[37]
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- Trinuclear copper(I) pyrazolate efficiently catalyses CuAAC under mild
conditions
- Copper(I) macrocycle plays a role of a bifunctional catalytic system
- Rate-determining step of the reaction is the azide migratory insertion
- RDS of CuAAC reactions can depend on catalytic system and substrate class
- Catalytic system is applicable for the synthesis of amino acids bearing
triazole motif
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