Tris-isocyanide copper(I) complex enabling copper azide-alkyne cycloaddition in neat conditions

Article abstract of DOI:10.1002/aoc.6401

The three-coordinated homoleptic Cu(I) complex with 2,6-dimethylphenyl isocyanide in the coordination sphere was easily synthesized and isolated as tetrafluoroborate salt. The structure of the compound was determined by single-crystal X-ray diffraction. T

Full text of DOI:10.1002/aoc.6401

Received: 19 June 2021
DOI: 10.1002/aoc.6401
Revised: 26 July 2021
Accepted: 26 July 2021
R E S E A R C H A R T I C L E
Tris-isocyanide copper(I) complex enabling copper
azide-alkyne cycloaddition in neat conditions
Valentina Ferraro1
Valentina Beghetto1,2,3
| Roberto Sole1
| Jesús Castro4
| Marco Bortoluzzi1,2
|
1Dipartimento di Scienze Molecolari e
Nanosistemi, Università Ca' Foscari,
Venice, Italy
2Consorzio Interuniversitario Reattività
Chimica e Catalisi (CIRCC), Bari, Italy
The three-coordinated homoleptic Cu(I) complex with 2,6-dimethylphenyl
isocyanide in the coordination sphere was easily synthesized and isolated as
tetrafluoroborate salt. The structure of the compound was determined by
single-crystal X-ray diffraction. The complex is highly stable, active and selec-
tive toward the copper-catalyzed azide-alkyne cycloaddition, working in neat
conditions and in the absence of bases at room temperature. Substrate scope
was assessed by testing several different alkynes and azides. In most cases the
corresponding 1,4-disubstituted-1,2,3-triazoles were isolated in high yields.
3Crossing srl, Treviso, Italy
4
ꢀ
Departamento de Química Inorganica,
Universidade de Vigo, Facultade de
Química, Edificio de Ciencias
Experimentais, Vigo, Spain
Correspondence
K E Y W O R D S
Valentina Ferraro and Roberto Sole,
Dipartimento di Scienze Molecolari e
Nanosistemi, Università Ca' Foscari
Venezia, Via Torino 155, I-30172, Mestre
(VE), Italy.
click reaction, copper(I), CuAAC, isocyanide, trigonal planar
Email: valentina.ferraro@unive.it;
roberto.sole@unive.it
Funding information
Università Ca' Foscari Venezia, Grant/
Award Number: Bando Spin 2018, D. R.
1065/2018 prot. 67416
1 | INTRODUCTION
Despite the massive number of reports present in the
literature, the development of new catalytic systems
Since 2001, when K. B. Sharpless coined the term
“Click Chemistry” referring to a class of high yielding
organic reactions based on few simple steps, copper
still represents an attracting topic, especially in view of
the implementation of the sustainability of processes to
be employed also at industrial level.[4–21]
azide-alkyne cycloaddition (CuAAC) emerged as
a
According to the literature, the most common condi-
tions adopted for copper azide-alkyne cycloaddition
powerful tool enabling the synthesis of triazoles.[1–4]
The tremendous impact gained by CuAAC mostly
relies on the wide use of 1,4-disubstituted-
1,2,3-triazoles for a plethora of applications ranging
from the synthesis of pharma,[5–10] polymers,[11–14] and
natural compounds,[9] to the preparation of ligands for
organometallic chemistry and catalyst design.[15–20]
involve the use of
a Cu(II) precursor, such as
CuSO4ꢀ5H2O or Cu(OAc)2, generating in situ the active
Cu(I) species in the presence of sodium ascorbate as
reducing agent and water/alcohol mixture as solvent
(Scheme 1a).[22] The low cost of the reagents and the
wide substrate applicability made this catalytic system
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2021 The Authors. Applied Organometallic Chemistry published by John Wiley & Sons Ltd.
Appl Organomet Chem. 2021;e6401.
wileyonlinelibrary.com/journal/aoc
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https://doi.org/10.1002/aoc.6401

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FERRARO ET AL.
CuAAC.[16,19,20] The growing attention toward iso-
cyanides as supporting and non-innocent ligands in
metal catalysis focused our studies on new
Cu(I) isocyanide derivatives.[33] Thus, in this paper we
report the synthesis and structural characterization of a
rare example of three-coordinated Cu(I) homogeneous
catalyst having formula [Cu(CNXyl)3][BF4], where
CNXyl is 2,6-dimethylphenyl isocyanide.[34–37] Remark-
able catalytic activity for CuAAC in neat conditions was
verified with a wide number of substrates (Scheme 1c).
2 | RESULTS AND DISCUSSION
2.1 | Synthesis and characterization
SCHEME 1 (a) General conditions of copper azide-alkyne
cycloaddition (CuAAC) in presence of Cu(II) salts; (b) general
conditions of CuAAC in presence of Cu(I) catalysts; (c) this work
the most frequently used. On the contrary, the direct
addition of Cu(I) metal sources such as copper halides or
triflate is less straightforward. In fact, in order to favor
the formation of Cu(I) species, bulky organic ligands,
mainly phosphines, are added to stabilize the precursors,
to prevent the disproportionation and to increase the sol-
ubility in organic media (Scheme 1b).[4] Furthermore, it
is widely accessible that the use of a base is beneficial,
increasing the turnover of the reaction.[23]
The complex [Cu(CNXyl)3][BF4] was prepared by addi-
tion of three equivalents of 2,6-dimethylphenyl
isocyanide to the acetonitrile complex [Cu(NCCH3)4]
[BF4], under mild conditions (see Scheme 2). The
elemental analysis supported the proposed formula and
conductivity measurements indicated that the complex
behaves as 1:1 electrolyte in acetone solutions. IR and 1H
NMR spectra confirmed the disappearance of the coordi-
nated acetonitrile and the coordination of isocyanides. In
particular, the band at 2170 cmꢁ1 related to the νC ≡ N
stretching is diagnostic for the coordinated isocyanide.
The presence of the counterion is confirmed by a strong
Hence, the availability of an air-stable Cu(I) complex
active in CuAAC allowing to reduce or avoid the use of
reductants, bases, solvents, and phosphines is highly
attractive in terms of process sustainability. C-donor
ligands such as isocyanides and N-heterocyclic carbenes
(NHC) represent promising and versatile choices to
replace phosphines in the coordination sphere of
Cu(I) catalytically active complexes.[24–28] For instance,
Liu and Reiser reported the synthesis of a polymeric com-
plex starting from CuCl and 2,4-dimethoxyphenyl
isocyanide active toward CuAAC in heterogeneous
conditions. Among the advantages, the catalyst could be
recovered by filtration and recycled up to five times
without loss of activity.[29] The synthesis of 1,2,3-triazoles
in heterogeneous catalytic conditions is of current
interest, as demonstrated by the recent reports on cata-
lysts composed by Cu nanoparticles on carbon nanotubes
or Cu(II)-coated magnetic core-shell nanoparticles
Fe3O4@SiO2 modified by isatoic anhydride.[30,31] For
what concerns Cu(I)-NHC complexes, it is worth noting
that NMR and DFT studies revealed that the dissociated
NHC ligands are able to deprotonate the coordinated
phenylacetylene, favoring the formation of the Cu(I)-
acetylide intermediate.[32]
1
band between 1085 and 985 cmꢁ1. As regards the H
NMR spectrum, the methyl protons are associated to a
singlet at 2.51 ppm (13C HSQC 18.74 ppm). The aromatic
protons generate one doublet centered at 7.19 ppm (13C
HSQC 128.23 ppm) related to the meta-positions and one
triplet at 7.32 ppm (13C HSQC 130.33 ppm) for the para-
position. The ipso-carbons in ortho-positions of the xylyl
ring are associated to a singlet at 135.86 ppm in the 13C
NMR spectrum, while a weak, slightly broad resonance
centered around 149.1 ppm is attributable to the coordi-
nated carbon atoms, shifted at lower frequency with
respect to the free ligand (169.5 ppm), as already
observed in the literature.[38] IR and NMR data are in line
with those reported for the comparable halide-complex
[CuBr(CNXyl)3].[39] NMR and IR spectra are provided in
the Supporting Information, Figures S1 and S2.
The complex exhibits good thermal stability
(decomposition starts around 170ꢂC) and no appreciable
oxidation can be detected under air at room temperature.
Electrochemical measurements in CH3CN/LiClO4
solution showed two irreversible oxidation processes,
with peaks around 1.48 and 1.74 V versus Fc+/Fc using a
glassy carbon electrode and a scan rate of 500 mV/s. A
shoulder around ꢁ2.07 V and an irreversible peak
centered at ꢁ2.45 V versus Fc+/Fc were observed by
The interest of our research group toward the synthe-
sis of new triazolyl-containing species prompted us to
prepare new and more sustainable Cu(I) organometallic
complexes and to test their performances toward

FERRARO ET AL.
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SCHEME 2 Synthesis of [Cu(CNXyl)3][BF4]
recording cyclic voltammograms at negative potentials.
The reduction processes are not related to the previous
oxidation of the compound. The comparison with the
cyclic voltammograms obtained for the free isocyanide
under the same experimental conditions suggests that the
first oxidation process of [Cu(CNXyl)3][BF4] may be
attributed to the coordinated ligands, while the reduction
processes probably involve the metal center. Selected
cyclic voltammograms are collected in Figure S3,
Supporting Information. Similar results were obtained by
studying the oxidation of [Cu(CNXyl)3][BF4] and CNXyl
with a gold electrode, despite the fact that the processes
occur at lower potentials. In particular, in the case of
[Cu (CNXyl)3][BF4] a first irreversible oxidation process
centered around 1.02 V versus Fc+/Fc is followed by a
second oxidation peak at 1.29 V, the latter associated to
a reverse peak at 0.59 V. The isocyanide showed under
the same experimental condition an irreversible process
with maximum at 1.24 V (see the inset of Figure S3,
Supporting Information).
FIGURE 1 Crystal structure of [Cu(CNXyl)3][BF4]. Ellipsoids
are drawn at 50% level. Inset: dimeric units formed by π,π-stacking
interactions
formally triple C ≡ N bond in the isocyanide ligand is
1.15 Å long (see Table 1), slightly more elongated than
the value found for [Cu(MIBI)3][BF4], equal to 1.142
(4) Å. On the other hand, because of the sp2 character of
the carbon atoms of the aryl fragment, the formally single
N-C bond is slightly shorter (1.40 Å) if compared to the
MIBI derivative (1.435(4) Å).[41] Similar values were
found for the [CuBr(CNXyl)3] complex.[39]
2.2 | Crystal structure determination
and DFT studies
Crystals of [Cu(CNXyl)3][BF4] suitable for X-ray determi-
nation were collected from dichloromethane/diethyl
ether solutions. The compound crystallized in the P21/c
space group. Crystal data and parameters related to the
refinement of the structure are collected in Table S1,
Supporting Information. As observable in Figure 1,[40]
the cation consists of a three-coordinated copper(I) com-
pound with three 2,6-dimethylphenyl isocyanide ligands.
The Cu atom lies on a non-crystallographic threefold axis
and it is bonded to three ligands in a trigonal-planar
fashion. This coordination mode was also found in the
compound with 2-methoxyisobutylisocyanide (MIBI)
ligands [Cu(MIBI)3][BF4].[41] The Cu-C bond lengths
range from 1.9078(14) to 1.9188(14) Å (see Table 1), and
are in good agreement with the value measured for the
[Cu(MIBI)3]+ cation, equal to 1.917(3) Å. The bond
lengths are instead shorter than those found in the
tetracoordinated and neutral [CuBr(CNXyl)3] complex,
comprised between 1.924(2) and 1.946(2) Å.[39] The
As already observed for [Cu(MIBI)3]+ and
[Cu2(μ-L)3]2+ (L = 1,10-diisocyanoferrocene),[41,42] [Cu
(CNXyl)3]+ is not perfectly trigonal, the C-Cu-C angles
being 116.12(6), 117.31(6) and 125.96(6)ꢂ. The sum,
359.4ꢂ, reveals however the planarity of the first coordi-
nation sphere and the copper atom is only 0.086(1) Å
above the plane defined by the three donor atoms. Never-
theless, the xylyl planes are not coplanar as shows
Figure S4 (Supporting Information). The benzene ring
planes form dihedral angles of 4.15(2) (between #1 and
#2) 8.17(3) (between #2 and #3) and 10.45(2)ꢂ (between
#1 and #3). Such a behavior could be related to supramo-
lecular interactions (vide infra).
The Cu-C-N arrangements are also not exactly linear,
with angles ranging from 171.37(12) to 176.56(13)ꢂ.
Similar values were found also for the tetracoordinated
derivative [CuBr(CNXyl)3],[39] much more bent than the
Cu-C-N angles in the tetracoordinated complex

4 of 10
FERRARO ET AL.
TABLE 1 Selected bond lengths [Å] and angles [ꢂ] for [Cu(CNXyl)3][BF4]
Cu-C(11)
1.9078(14)
1.9188(14)
1.1511(18)
1.1521(18)
1.1494(18)
125.96(6)
Cu-C(21)
1.9127(14)
Cu-C(31)
C(11)-N(11)
N(11)-C(12)
N(21)-C(22)
N(31)-C(32)
C(11)-Cu-C(31)
1.4039(17)
1.4036(16)
1.3991(17)
117.31(6)
C(21)-N(21)
C(31)-N(31)
C(11)-Cu-C(21)
C(21)-Cu-C(31)
N(11)-C(11)-Cu
N(21)-C(21)-Cu
N(31)-C(31)-Cu
116.12(6)
171.37(12)
174.73(12)
176.56(13)
C(11)-N(11)-C(12)
C(21)-N(21)-C(22)
C(31)-N(31)-C(32)
174.63(14)
175.68(13)
178.86(14)
[Cu2(ox)2(CNXyl)4] and in other isocyanide derivatives
such as [Cu(CNtBu)4]+ or the above mentioned [Cu
(MIBI)3]+ cation.[41,43,44]
The presence of the tetrafluoroborate anion allows
the formation of several non–classical C-HꢀꢀꢀF bonds that
probably maintain the supramolecular network, since
three of the four fluorine atoms are involved. The param-
eters are set out in Table S2, Supporting Information (see
also Figure S5, Supporting Information). Other secondary
bonds can be found in the crystal structure. Noteworthy
is the π,π-stacking interaction between two xylyl moie-
ties. Such an interaction, shown in the inset of Figure 1,
is double and generates dimeric units. The distance
between centroids is 3.7172(8) Å and the dihedral angle
between planes is 4.14(7)ꢂ, so one of the centroids is at
only 3.4409(5) Å from the other plane, but the ring is
slipped of 1.601 Å with symmetry operation 1-x, 1-y, 1-z.
The third xylyl ring is implicated in a stair-like or zig-zag
growing along the c axis due to an interaction between
the π cloud and the metal of a neighbor complex situated
at 3.41 Å with symmetry operation x, 3/2-y, z-1/2, as
shows Figure S6 (Supporting Information). The shorter
Cu-Cu distance found in the compound is 7.431 Å,
supported by this interaction. The unit cell contents are
set out in Figure S7 (Supporting Information).
The structure of the molecule in a low polar solvent
(ε = 3.0) was simulated by means of C-PCM/DFT
calculations. The central {CuC3} fragment is roughly
superimposable to that determined by X-ray diffraction,
as observable in Figure 2. On the other hand, the lack of
the intramolecular interactions previously described cau-
ses a rotation of the aryl substituents that are much more
perpendicular to the {CuC3} plane with respect to the
X-ray structure. The tetrafluoroborate ion is quite close to
Cu(I), being the shorter Cu---F distance 2.290 Å, but the
molecule maintains the trigonal planar arrangement,
being the Cu(I) only 0.125 Å far from the plane deter-
mined by the three coordinated carbon atoms.
FIGURE 2 Superimposition of the DFT-optimized (red tones)
and X-ray (green tones) structures of [Cu(CNXyl)3][BF4]. Selected
computed bond lengths (Å): Cu-C, 1.963, 1.966, 1.967; Cu---F,
2.290; C ≡ N, 1.164, 1.164, 1.165. Selected computed angles (ꢂ):
C-Cu-C, 118.2, 120.2, 120.4
Since alkynes were used as solvents in most of the
catalytic runs described below, the possible complex
formed by [Cu(CNXyl)3][BF4] with phenylacetylene was
computationally investigated. The DFT-optimized
structure of [Cu(CNXyl)3(HC ≡ CPh)][BF4] is reported
in Figure 3. The reaction [Cu(CNXyl)3][BF4]
+ HC ≡ CPh ! [Cu(CNXyl)3(HC ≡ CPh)][BF4] is associ-
ated to
a
negative enthalpy variation equal to
ꢁ4.6 kcal molꢁ1 but, because of the reduction of
molecularity, the estimated Gibbs energy variation is pos-
itive, +6.3 kcal molꢁ1. Accordingly, no meaningful
change in the H, 19F and 11B chemical shift values was
1
observed by adding one equivalent of phenylacetylene to
a CDCl3 solution of [Cu(CNXyl)3][BF4]. The NMR
spectra are provided in the supporting information,
Figures S8–S10 (Supporting Information). On the other
hand, the high concentration of alkyne in the catalytic
runs makes possible the formation in solution of the

FERRARO ET AL.
5 of 10
isocyanide as in situ base was investigated, first suppos-
ing the formation of the acetylide-complex [Cu(C ≡ CPh)
(CNXyl)2] and [HCNXyl][BF4] after the coordination of
phenylacetylene to [Cu(CNXyl)3][BF4]. It was also con-
sidered the deprotonation of coordinated HC ≡ CPh by
free isocyanide, possibly derived from the dissociation
from another molecule of complex. The reaction studied
in this last case is [Cu(HC ≡ CPh)(CNXyl)3][BF4]
+ CNXyl ! [Cu(CCPh)(CNXyl)3] + [HCNXyl][BF4]. In
the first situation the Gibbs energy variation is
37.7 kcal molꢁ1, while the second reaction is associated
to a Gibbs energy variation of 20.5 kcal molꢁ1. The
strongly positive ΔG values rule out the possible behavior
of isocyanide as base.
FIGURE 3 DFT-optimized structure of [Cu
(CNXyl)3(HC ≡ CPh)][BF4]. Color map: Cu, orange; N, blue; C,
gray; F, yellow; B, pink. Selected (3,-1) b.c.p. are shown in green.
Electron density (ρ) and potential energy density (V) values at
b.c.p. (a.u.): Cu---C, ρ = 0.030, V = ꢁ0.029; H---F, ρ = 0.026,
2.3 | Catalytic activity
V = ꢁ0.021. Selected computed bond lengths (Å): Cu-Cisocyanide
1.966, 1.983, 1.989; Cu-Calkyne 2.491, 2.652; H---F, 1.891; C ≡ N,
,
1.163, 1.164, 1.165. Selected computed angles (ꢂ): C-Cu-C, 112.0,
115.3, 122.2
With the fully characterized complex in hand, we evalu-
ated its catalytic activity toward the copper azide-alkyne
cycloaddition. The reaction between benzyl azide (1) and
phenylacetylene (2) to afford 1-benzyl-4-phenyl-1H-1,-
2,3-triazole (T1) was initially chosen (see Table 2). Given
the easy purification process of T1, obtained by simply
washing the solid formed during the reaction, optimiza-
tion was evaluated in terms of isolated yields.
Initially, the conditions generally employed for
CuAAC were tested (Table 2, Entry 1).[16,19,20] T1 was
recovered in 72% isolated yield from a water/methanol
1:1 mixture containing 1 mol% of catalyst after 18 h of
reaction time. The selectivity toward the 1,4-disubstituted
regioisomer was complete since no traces of 1,5 reg-
ioisomer were detected. Similar yield of T1 was achieved
by reducing the reaction time to 6 h (Table 2, Entry 2),
allowing us to set this reaction time as starting point for
further optimization experiments.
While the use of water alone (Table 2, Entry 3) or
methanol (Table 2, Entry 4) still allowed to recover T1 in
good yields, dichloromethane afforded poor yields
(Table 2, Entry 5), probably because of the formation of
chlorinated Cu-species which slowed down the reaction
as previously described in the literature.[46]
Surprisingly, it was observed that the reaction
proceeded faster when no solvent was employed (Table 2,
Entry 6). In fact, [Cu(CNXyl)3][BF4] revealed to be solu-
ble in the reaction mixture obtained by mixing 1 and 2.
In the absence of a solvent, the reaction stopped as the
product gradually formed as a white solid. Two hours
were sufficient to reach almost quantitative yields of the
desired product T1 (Table 2, Entry 7). For comparison,
the CuSO4ꢀ5H2O/sodium ascorbate catalytic system
under the same experimental conditions afforded T1 in
32% yield.
complex depicted in Figure 3. AIM[45] calculations
highlighted the presence of two (3,-1) bond critical points
(b.c.p.), connecting the phenylacetylene with Cu(I) and
the [BF4]ꢁ anion. [Cu(CNXyl)3(HC ≡ CPh)][BF4] is less
planar than the precursor, being the Cu(I) center 0.381 Å
far from the plane determined by the isocyanide donor
atoms. The H---F interaction is associated to a slight
activation of the phenylacetylene C-H bond, longer in the
complex (1.089 Å) with respect to the free molecule
optimized at the same computational level (1.077 Å). The
electron density at (3,-1) C-H b.c.p. decreases upon
coordination from 0.279 to 0.274 a.u., and accordingly,
the potential energy density is less negative (ꢁ0.339 a.u.
in the complex, ꢁ0.343 a.u. in the free phenylacetylene).
The (3,-1) C-H b.c.p is closer to the hydrogen atom in the
complex (0.332 Å) than in the free molecule (0.368 Å),
suggesting an increase of acidity.
The possible interaction of the tetrafluoroborate
anion with coordinated phenylacetylene could explain
the broadening of the 19F NMR resonance observed by
collecting the spectrum using phenylacetylene as solvent
(CDCl3 as external standard). The comparison of the 19F
NMR spectrum with that recorded for a CDCl3 solution
of the complex is shown in Figure S11, Supporting
Information. Comparable FWHM values were instead
observed for the 11B NMR resonance in phenylacetylene
and CDCl3 (Figure S11, Supporting Information).
Despite that the full comprehension of the mecha-
nism involved in the catalytic activity described below is
beyond the scope of this work, the possible behavior of

6 of 10
FERRARO ET AL.
TABLE 2 Optimization of reaction conditions between benzyl azide (1) and phenylacetylene (2)
Entrya
Solvent (ml)
Time (h)
Yield (%)b
1
H2O (1)/MeOH (1)
18
6
72
71
71
66
32
98
96
55
93
94
92
2
H2O (1)/MeOH (1)
3
H2O (1)
6
4
MeOH (1)
6
5
DCM (1)
6
6
/
6
7
/
2
8c
9c
10c
11c
/
2
/
12
12
12
THF
Toluene
aReaction conditions 1 = 1 mmol; 2 = 1.1 mmol; cat. = 1 mol% T = r.t.
bIsolated yield.
cCat. = 0.1 mol%.
When the catalyst loading was reduced to 0.1 mol%
T1 was obtained in lower yields after 2 h (Table 2,
Entry 8), and as at least 12 h were required to reach yield
> 90% under these conditions (Table 2, Entry 9). The
TON value corresponding to Entry 9 (Table 2) is 930. In
order to verify if the reaction was limited by the precipita-
tion of the product, we carried out further catalytic runs
considering THF and toluene as solvents (Table 2, Entries
10 and 11). The TON values obtained were 940 (THF)
and 920 (toluene), closely comparable to the result
obtained in neat conditions.
Despite the fact that the deep investigation of the role
of the counter-anion is beyond the scopes of the present
work, we tried to add a stoichiometric amount of lithium
triflate to the reaction mixture, considering the reaction
conditions of Table 2, Entry 6. The yield of T1 after 2 h
was around 56% and only after 12 h 78% was achieved.
The addition of lithium triflate revealed therefore to be
detrimental for the catalytic activity and it was no further
investigated.
library of 1,4-disubstituted-1,2,3-triazoles as reported in
Scheme 3.
The presence of a sterically hindered donating group
on phenylacetylene did not slow down the reaction, as
93% of T2 was isolated. The same performances were
maintained in the presence of aliphatic alkynes (T3 and
T4).
CuAAC failed when alkynes bearing a terminal
hydroxyl groups were tested (T5 and T6) probably due to
coordination of the oxygen atom to the metal center. This
assumption was verified by protection of the -OH moiety
with an acetate group allowing to overcome this draw-
back, as testified by the high yielding reactions between
benzyl azide and methyl propiolate (T7) and propargyl
acetate (T8). Additionally, when propargyl chloride was
employed, good yields of the corresponding triazole were
obtained (72%, T9). A possible explanation is that the
hydroxyl-substituted fragments may behave as donor
groups toward Cu(I) species in the experimental condi-
tions described, thus inhibiting the catalytic activity of
the complex.
Further experiments were carried out in the best
reaction conditions, that is, 2-h reaction time, 1 mol%
catalyst loading and solvent-free, to verify the robustness
of the optimized catalytic system. Consequently, different
azides and terminal alkynes were tested to achieve a wide
Different aliphatic azides were also tested, demon-
strating that the reaction proceeded with good tolerance
toward different functional groups. As a matter of fact,
2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethan-1-amine
(T10)

FERRARO ET AL.
7 of 10
SCHEME 3 Triazoles synthesized using
[Cu(CNXyl)3][BF4] as catalyst and isolated
yields. Reaction conditions: azide = 1 mmol;
alkyne = 1.1 mmol; cat. = 1 mol%; r.t, 2 h
was recovered in excellent yields, despite the fact
that amine moieties could display affinity toward
Cu(I) species, as previously verified for hydroxyl
functional groups. Finally, the reaction of ethyl
4-azidopentanoate with but-3-ynyl methanesulfonate and
tert-butyl azide with propargyl acetate afforded the
triazoles T11 and T12 (see Scheme 3) with yields above
80%. The activity of the catalyst toward most of the sub-
strates is comparable to similar reports making use of
Cu(I) catalysts using phosphine ligands and/or amine
bases.[47,48] Characterization data of the isolated triazoles
are reported in the supporting information (Table S3,
experimental conditions, such as room temperature and
absence of solvents and co-reactants. The catalyst rev-
ealed to be tolerant toward a wide variety of substrates
and highly selective. NMR experiments suggested the
presence of only one species in solution, and the stability
observed was corroborated by electrochemical measure-
ments. The one-pot synthesis of the complex, carried out
with quite common reactants, makes it a suitable alter-
native for the catalytic synthesis of triazoles. Finally, the
possibility of different functionalizations of isocyanides
and the use of different counter-anions open the pro-
spective to develop further catalysts with improved
features.
1
Supporting Information) together with H and 13C {1H}
NMR spectra (Figures S12–S35, Supporting Information).
Finally, the preliminary test carried out with 2-butyne
in combination with benzyl azide in neat condition
showed no conversion of the substrates; therefore, the
catalytic study was not further extended to non-terminal
alkynes.
4 | EXPERIMENTAL SECTION
4.1 | Materials and methods
Commercial solvents (Aldrich) were purified following
reported procedures in order to be used inside the glove
box.[49] [Cu (NCCH3)4][BF4] was obtained from Cu2O
3 | CONCLUSIONS
following
a
reported synthesis.[50] Benzyl azide,[51]
In this work we described the straightforward synthesis
2-azidoethylamine,[52] tert-butyl azide[53] and ethyl
5-azide valerate[54] were synthesized following literature
procedures. Alkynes were provided by Sigma Aldrich and
used as received. The other reagents were Aldrich, TCI or
Carlo Erba products used as received.
and
characterization
of
a
three-coordinated
Cu(I) isocyanide complex with trigonal planar geometry,
as ascertained by single-crystal X-ray diffraction. The
catalytic tests provided clearly indicated noteworthy
catalytic activity toward the azide-alkyne cycloaddition,
and the most intriguing features are related to the
The synthesis of the complex was carried out under
inert atmosphere in a glove box (MBraun Labstar with

8 of 10
FERRARO ET AL.
MB 10 G gas purifier) filled with N2 and equipped for
inorganic syntheses.
concerning crystal data and structural refinement are
given in Table S1, Supporting Information. CCDC
2073393 contains the supplementary crystallographic
data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Cen-
tre via www.ccdc.cam.ac.uk/data_request/cif. PLATON
(version 60720) was used to obtain some geometrical
parameters of the cif file.[59]
Elemental analyses (C, H, N) were carried out using
an Elementar Unicube microanalyzer. Conductivity mea-
surements in acetone were conducted with a Radiometer
Copenhagen CDM83 instrument. Melting point measure-
ments were carried out using a modified Falc 360 D appa-
ratus equipped with a video recording device. IR spectra
(KBr pellets) were collected in the 4000–400 cmꢁ1 range
using a PerkinElmer Spectrum One spectrophotometer.
Monodimensional nuclear magnetic resonance (NMR)
spectra were collected at variable temperature employing
Bruker Avance 300 and Avance 400 instruments operat-
ing respectively at 300.13 MHz and 400.13 MHz of 1H res-
4.3 | Computational details
The structures of the compounds were optimized using
the range-separated ωB97X DFT functional[60–62] in com-
bination with Ahlrichs' split-valence polarized basis set
(def2-SVP).[63] The C-PCM implicit solvation model was
added to ωB97X calculations, considering ε = 3.0.[64,65]
The stationary points were characterized by IR simula-
tions (harmonic approximation), from which zero-point
vibrational energies and thermal corrections (T = 298 K)
were obtained.[66] Calculations were carried out using
Gaussian 09[67] and the output files were analyzed with
Multiwfn, version 3.5.[68] Cartesian coordinates of the
DFT-optimized structures are provided in a separated .
xyz file.
1
onance. H and 13C {1H} NMR spectra are referred to the
partially non-deuterated fraction of the solvent, itself
quoted to tetramethylsilane. 11B and 19F NMR resonances
are respectively referred to BF3ꢀEt2O and CCl3F. Cyclic
voltammetry measurements were performed using an
eDAQ ET014-199 instrument in acetonitrile containing
0.1 M LiClO4. The solvent was purified following
common techniques[49] and all the measurements were
carried out under argon at room temperature. The work-
ing electrodes were 1-mm glassy carbon or gold disks,
while the auxiliary electrode was Pt-coated titanium rod.
The electrodes were provided by eDAQ. Ferrocene was
introduced as internal standard and a Pt wire was used
as pseudo-reference electrode. ESI-MS analyses were
performed using a Finnigan LCQ-Duo ion-trap instru-
ment, operating in positive ion mode (sheath gas N2,
source voltage 4.0 KV, capillary voltage 21 V, capillary
temperature 200ꢂC).
4.4 | Synthesis of the complex
The complex was synthesized by slowly adding
2,6-dimethylphenyl isocyanide (125 mg, 0.954 mmol) to a
dichloromethane solution (20 mL) containing 100 mg
(0.318 mmol) of [Cu(NCCH3)4][BF4]. The solution was
stirred overnight, then the solvent was evaporated under
reduced pressure. The addition of diethyl ether (about
5 ml) caused the precipitation of a solid that was filtered
and dried in vacuo. The complex was crystallized from
dichloromethane/diethyl ether solutions. Yield > 75%.
Despite the fact that the complex was synthesized under
controlled atmosphere, it revealed to be air stable at room
temperature.
4.2 | X-ray structure determination
Crystallographic data were collected at CACTI
(Universidade de Vigo) at low temperature using a
Bruker D8 Venture with a CMOS Photon 100 detector
and Mo-Kα radiation (λ = 0.71073 Å) equipped with a
CryoStream 800 system. The software APEX3[55] was
used for collecting frames of data, indexing reflections,
and the determination of lattice parameters,
SAINT[55] for integration of intensity of reflections, and
SADABS[55] for scaling and empirical absorption correc-
tion. Further crystallographic treatment was performed
with the Oscail program.[56] The structure of the com-
pound was solved by using the SHELXT program[57]
and refined by a full-matrix least squares based on F2,
SHELXL program.[58] Non-hydrogen atoms were refined
with anisotropic displacement parameters. Hydrogen
atoms were included in idealized positions and refined
with isotropic displacement parameters. Further details
Characterization of [Cu(CNXyl)3][BF4]. Elemental
analysis for C28H29BCuF4N3 (543.86
g , %),
molꢁ1
calcd: C, 60.28, H, 5.24,ꢂ N, 7.53. Found: C, 60.04, H,
5.26, N, 7.50. M.p.: 170 C (dec.). ΛM (acetone, 298 K,
ohmꢁ1 molꢁ1 cm2): 171. IR (KBr, cmꢁ1): 3080–
2990 m/w (aromatic
2170 s (νC ≡ N); 1085–985 s (νBF4). 1H NMR (CDCl3,
298 K) 7.32 (t, HH = 7.6 Hz, 3H, CH), 7.19
νC-H), 2955–2850 m/w (νC-H);
δ
J
(d, JHH = 7.6 Hz, 6H, CH), 2.51 (s, 18H, CH3). 13C
{1H} NMR (CDCl3, 298 K) δ 149.1 (s, br, Cisocyano),
135.86 (s, Cipso), 130.33 (s, CHpara), 128.23 (s, CHmeta),
18.74 (s, CH3).

FERRARO ET AL.
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(1.0 mmol), alkyne (1.1 mmol) and complex [Cu
(CNXyl)3][BF4] (0.1–1 mol%) were added in this order.
The reaction was then allowed to proceed at room
temperature and monitored via TLC. After the total
consumption of the starting azide, the solid product was
collected by filtration and washed with hexane. When
the corresponding triazole was an oil, the reaction mix-
ture was concentrated under vacuum and the residue
was finally purified on silica gel (hexane/ethyl acetate).
Yields reported are an average of at least two experi-
ments. Characterization data of the synthesized triazoles
are collected in the Supporting Information, Table S3.
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ACKNOWLEDGMENTS
CACTI (University of Vigo) is gratefully acknowledged
for X-ray data collection. Università Ca' Foscari Venezia
is gratefully acknowledged for financial support (Bando
Spin 2018, D. R. 1065/2018 prot. 67416).
AUTHOR CONTRIBUTIONS
[15] B. M. J. M. Suijkerbuijk, B. N. H. Aerts, H. P. Dijkstra, M.
Lutz, A. L. Spek, G. Van Koten, R. J. M. Klein Gebbink,
J. Chem. Soc. Dalton Trans. 2007, 1273.
[16] R. Sole, M. Bortoluzzi, A. Spannenberg, S. Tin, V. Beghetto,
J. G. de Vries, Dalton Trans. 2019, 48, 13580.
[17] D. Schweinfurth, L. Hettmanczyk, L. Suntrup, B. Sarkar,
Z. Anorg. Allg. Chem. 2017, 643, 554.
Valentina Ferraro: Formal analysis; investigation;
validation. Roberto Sole: Formal analysis; investigation;
validation. Marco Bortoluzzi: Conceptualization;
formal analysis; funding acquisition; supervision.
Valentina Beghetto: Conceptualization; formal analy-
sis; funding acquisition; supervision. Jesús Castro:
Formal analysis; investigation; supervision.
[18] H. Struthers, T. L. Mindt, R. Schibli, Dalton Trans. 2010,
39, 675.
[19] A. Scrivanti, R. Sole, M. Bortoluzzi, V. Beghetto, N. Bardella,
A. Dolmella, Inorg. Chim. Acta 2019, 498, 119.
[20] A. Scrivanti, M. Bortoluzzi, R. Sole, V. Beghetto, Chem. Pap.
2018, 72, 799.
[21] M. Meldal, F. Diness, Trends Chem. 2020, 2, 569.
[22] L. Liang, D. Astruc, Coord. Chem. Rev. 2011, 255, 2933.
[23] P. L. Golas, N. V. Tsarevsky, B. S. Sumerlin, K. Matyjaszewski,
Macromolecules 2006, 39, 6451.
DATA AVAILABILITY STATEMENT
The data that support the finding of this study are
available from the corresponding authors upon reason-
able request.
ORCID
Valentina Ferraro https://orcid.org/0000-0003-2694-
ꢀ
[24] S. Díez-Gonzalez, A. Correa, L. Cavallo, S. P. Nolan, Chem. A
2955
Eur. J. 2006, 12, 7558.
ꢀ
Roberto Sole https://orcid.org/0000-0002-3208-2288
Marco Bortoluzzi https://orcid.org/0000-0002-4259-
1027
Valentina Beghetto https://orcid.org/0000-0001-8799-
210X
[25] S. Díez-Gonzalez, E. D. Stevens, S. P. Nolan, Chem. Commun.
2008, 4747.
[26] A. Garg, N. Khupse, A. Bordoloi, D. Sarma, New J. Chem.
2019, 43, 19331.
[27] A. Garg, N. Borah, J. Sultana, A. Kulshrestha, A. Kumar, D.
Sarma, Appl. Organomet. Chem. 2021, e6298.
[28] K. Fauché, F. Cisnetti, Inorg. Chem. Acta 2021, 520, 120312.
[29] M. Liu, O. Reiser, Org. Lett. 2011, 13, 1102.
[30] M. Khoshnevis, H. Eshghi, Appl. Organomet. Chem. 2021,
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Jesús Castro https://orcid.org/0000-0001-6169-3822
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How to cite this article: V. Ferraro, R. Sole,
M. Bortoluzzi, V. Beghetto, J. Castro, Appl
Organomet Chem 2021, e6401. https://doi.org/10.
1002/aoc.6401
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