Copper(II)-dipicolinate-mediated clickable azide–alkyne cycloaddition in water as solvent

Article abstract of DOI:10.1080/00958972.2018.1435870

Copper(II)-dipicolinate complex [Cu^II(dipic)(H₂O)₂] (1) (H₂L?=?dipicolinic acid (H₂dipic)) was synthesized via oxidation of copper(I) iodide and pyridine-2,6-dicarboxylic acid in water and acetonitril

Full text of DOI:10.1080/00958972.2018.1435870

Journal of Coordination Chemistry
ISSN: 0095-8972 (Print) 1029-0389 (Online) Journal homepage: http://www.tandfonline.com/loi/gcoo20
Copper(II)-dipicolinate-mediated clickable azide-
alkyne cycloaddition in water as solvent
Lahoucine Bahsis, Hicham Ben El Ayouchia, Hafid Anane, Smail Triki, Miguel
Julve & Salah-Eddine Stiriba
To cite this article: Lahoucine Bahsis, Hicham Ben El Ayouchia, Hafid Anane, Smail Triki,
Miguel Julve & Salah-Eddine Stiriba (2018): Copper(II)-dipicolinate-mediated clickable
azide-alkyne cycloaddition in water as solvent, Journal of Coordination Chemistry, DOI:
10.1080/00958972.2018.1435870
To link to this article: https://doi.org/10.1080/00958972.2018.1435870
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Publisher: Taylor & Francis
Journal: Journal of Coordination Chemistry
DOI: http://doi.org/10.1080/00958972.2018.1435870
Copper(II)-dipicolinate-mediated clickable azide-alkyne cycloaddition in
water as solvent
LAHOUCINE BAHSIS†, HICHAM BEN EL AYOUCHIA†, HAFID ANANE†, SMAIL TRIKI*‡,
MIGUEL JULVE§ and SALAH-EDDINE STIRIBA*†§
†Laboratoire de Chimie Analytique et Moléculaire, LCAM, Faculté Polydisciplinaire de Safi,
Université Cadi Ayyad, Safi, Morocco
‡Laboratoire de Chimie, Electrochimie Moléculaires et Chimie Analytique, UMR CNRS 6521, Université de Brest,
BP 809, 29238 Brest, France
§Instituto de Ciencia Molecular/ICMol, Universidad de Valencia, C/Catedrático José Beltrán, 46980,
Valencia, Spain
A contribution dedicated to our friend Prof. J. Faus in recognition of his outstanding career.
Copper(II)-dipicolinate complex [CuIIL(H2O)2] (1) (H2L = dipicolinic acid (H2dipic)) was
synthesized via oxidation of copper(I) iodide and pyridine-2,6-dicarboxylic acid in water and
acetonitrile in the presence of glycine. Complex 1 was characterized by FT-IR and elemental
analysis and its structure confirmed by single crystal X-ray analysis. This complex is an efficient
precatalyst that mediates azide-alkyne cycloaddition reactions in water at room temperature
either in the absence or presence of a reducing agent. Compound 1-mediated azide-alkyne
cycloaddition affords alkyl/aryl substituted 1,2,3-triazole heterocycles in a regioselective manner
and excellent yields under very mild reaction conditions matching the criteria of greener
protocols.
Keywords: Dipicolinic acid; Copper; Homogenous catalysis; Click chemistry; Azide-alkyne
cycloaddition; 1,2,3-Triazoles
1. Introduction
Since its discovery by Huisgen, the azide-alkyne [3+2] cycloaddition reaction (AAC) has
become a good strategy for synthesis of 1,2,3-triazole heterocycles. The original non-catalyzed
*Corresponding authors. Email: stiriba@uv.es (S.-E. Stiriba); smail.triki@univ-brest.fr (S. Triki)
1

AAC reaction, known as Huisgen reaction, was characterized by slow rate and low selectivity
due to the high reaction kinetic barrier [1, 2]. Because of the high temperature used, the low
yields and also the lack of selectivity, Sharpless and Meldal introduced the copper(I)-catalyzed
azide-alkyne cycloaddition (CuAAC) that leads to effective and regioselective formation of
1,2,3-triazoles by using catalytic copper species [3-5]. Since then, this transformation becomes
the model reaction within the concept of “click chemistry” because it proceeds effectively under
mild conditions with high regioselectivity and with less work-up. The CuAAC reaction has been
widely applied in medicinal, biological, and materials chemistry [6-8]. Moreover, 1,2,3-triazole
molecules have been used in industrial applications, such as corrosion retarding agents, dyes,
chemical sensors and energetic materials [9-12].
Traditionally, the standard catalytic system of CuAAC consists of copper(II) salts with a
reducing agent (such as sodium ascorbate) [4a]. Later, it was reported that copper(I) salts could
be used directly for this reaction, usually with stabilizing ligands [4b]. Recently, Kuang et al.
discovered that under reducing agent free conditions, copper(II)-chelation undergoes much faster
CuAAC. In fact, the in situ formation of the catalytically active copper(I) species in alcoholic
media occurs by using chelating picolyl azide substrates [13]. The catalytic copper(I) species are
generated by reduction of copper(II) via either alcohol oxidation or alkyne homocoupling, or
both, during an induction period [14].
In the last decade, the development of new ligands bearing nitrogen and oxygen donors
has attracted attention in catalysis, organic synthesis and biologic activity, especially in terms of
stabilization of the metal center involved in such applications [15]. Dipicolinic acid (hereafter
noted as H2dipic), which was discovered in 1936, is now applied as bacterial spores [16] and
enzyme inhibitors [17]. It is characterized by its capability in serving as hydrogen bonding donor
and acceptor [18] and its deprotonated anions (Hdipic- and dipic2-) are well suited to build
networks in the context of the coordination chemistry of metal-organic frameworks because of
the presence of two carboxylate groups as substituents on 1,5 positions at the pyridyl ring. This
arrangement of potential donors provides several coordination modes as shown by the crystal
structures of its metal complexes [19-23]. Metal(II)-dipicolinate complexes were mainly
characterized by their antimicrobial activities [24, 25]. Bearing this in mind, we herein report the
synthesis and X-ray characterization of a new dipicolinate-containing copper(II) complex,
[CuIIL(H2O)2] (1) [26], together with its application as a greener, efficient precatalyst for the
2

synthesis of 1,4-disubstituted 1,2,3-triazoles in water at room temperature. This protocol allows
the synthesis of several 1,2,3-triazoles without need for an additional reducing agent. To the best
of our knowledge, this is the first application of a copper(II)-dipicolinate species as precatalyst in
click chemistry.
2. Experimental
2.1. Materials and methods
Dipicolinic acid (pyridine-2,6-dicarboxylic acid) and copper(I) iodide were purchased from
Sigma-Aldrich. All alkynes were commercially available and used without purification.
Anhydrous MgSO4 was used to dry organic extracts and all volatiles were removed under
reduced pressure. All reaction mixtures were monitored by TLC using commercial glass backed
thin layer chromatography (TLC) plates (Merck Kieselgel 60 F254) and spots were visualized by
UV light at 254 nm. FT-IR (4000-450 cm-1) spectra were recorded on a FTIR spectrophotometer
(FT-IR Nicolet 5700). 1H NMR and 13C NMR measurements were carried out in CDCl3 solvents
on a Bruker DRX-300 spectrometer. GC-MS spectra were performed with an Agilent 5973N
mass spectrometer equipped with capillary columns (split/splitless, pulsed split and pulsed
splitless) at the SCSIE (Servicio Central de Soporte a la Investigación Experimental) of the
University of Valencia. Melting points were determined in open capillaries using an Electro
thermal 9100.
2.2. Preparation of [CuIIL(H2O)2] (1)
Dipicolinic acid (0.5 mmol, 83.6 mg) was dissolved in glycine (0.5 mmol, 37.8 mg) and distilled
water (10 mL) at 60 °C. A solution of copper(I) iodide (0.5 mmol, 95 mg) in 8 mL of acetonitrile
was added to the reaction mixture. The resulting solution was stirred for 0.5 h at 60 °C then kept
at room temperature for two weeks to give blue blocks suitable for X-ray diffraction. They were
collected by filtration, washed several times with distilled water and dried at room temperature.
Yield: 80%. IR (KBr/cm-1): 3400 (O–H), 2911 (C–H), 1686, 1647, (C=O), 917, 775, 737, 594,
436. Anal. Calcd for C14H14Cu2N2O12 (1, 529.35 g/mol): C, 31.77; H, 2.67; N, 5.29. Found: C,
31.83; H, 2.75; N, 5.25%.
3

2.3. General procedure for the copper-catalyzed azide–alkyne cycloaddition
A 25 mL round bottom flask was charged with 1 (5 mol %), azide (1.2 mmol), terminal alkyne
(1 mmol) and water (2 mL). The mixture was stirred at room temperature and the reaction
progress monitored by TLC until the starting materials were consumed. The reaction mixture
was then extracted with ethyl acetate (3×15 mL) and the combined organic fractions were
washed with a saturated NaHCO3 solution (3×10 mL) and with brine (20 mL). After drying over
MgSO4 the ethyl acetate was removed under reduced pressure and the resulting 1,2,3-triazoles
were obtained without further purification. The structures of the 1,2,3-triazole molecules were
confirmed by NMR spectroscopy (1H, 13C NMR) and mass spectrometry.
2.4. Single crystal X-ray structure determination of [CuIIL(H2O)2] (1)
Single crystal X-ray studies were performed at 293 K using an Oxford Diffraction Xcalibur 2-
CCD diffractometer fitted with graphite monochromated MoKα radiation (λ = 0.71073 Å). A
blue prismatic single crystal of 0.28 × 0.16 × 0.13 mm3 was used to collect the data. The crystal
structure was solved by direct methods with the SHELXS program and refined on F2 by
weighted full matrix least-squares methods using the SHELXL program [27] All non-hydrogen
atoms were refined anisotropically, while the hydrogens of the dipicolinic anion, located in
difference Fourier maps, were refined isotropically; the hydrogens of coordinated water were not
found. Crystallographic data and refinement details are depicted in table 1S (Supplementary
Information) whereas selected bond lengths and angles are listed in table 1.
3. Results and discussion
3.1. Synthesis and characterization
Copper(II)-dipicolinate complex [CuIIL(H2O)2] (1) was synthesized via oxidation of copper(I)
iodide and dipicolinic acid in water and acetonitrile in the presence of glycine (scheme 1).
Glycine was used to form water soluble copper(II) systems from the insoluble cuprous(I) ones
[28] that react readily directly with the dipicolinic acid without need to form the corresponding
salt of the diacid as previously reported [26]. The final copper(II)-dipicolinate complex was
obtained after slow evaporation, as blue single crystals in good yield (80%), equal to the one
reported by reacting dipicolinic acid and copper(II) sulfate in water and acetonitrile [29].
Compound 1, which is soluble in acetone and ethanol and slightly soluble in water, was already
4

prepared by reaction of the disodium salt of dipicolinic acid and copper(II) sulfate in a 1:1 molar
ratio in water under boiling conditions and crystallization by cooling at low temperature [26]. It
was characterized by FT-IR spectroscopy, elemental analysis and its structure elucidated by
single crystal X-ray crystallography.
O
O
O
O
Glycine
+
CuI
N
N
H2O / CH3CN
60 ºC
O
O
OH
OH
Cu
OH2
H2O
Complex
Dipicolinic acid
1
Scheme 1. Preparative route of 1.
FT-IR spectra of the dipicolinic acid (H2L) and 1 are shown in figure 1. The FT-IR spectrum of 1
shows a strong band at 3400 cm-1, identical to the one previously reported, which corresponds to
both asymmetric and symmetric O-H stretching vibrations, confirming the presence of water in
the complex [26]. The coordination of water to copper(II) in 1 is evidenced by the rocking and
wagging peaks observed at 917, 775 and 737 cm-1 of the hydroxyl groups [29]. In addition, the
absorption bands near 1686 and 1647 cm-1, which are attributed to the asymmetric stretching
vibration of carboxylate groups, indicate that the band for the stretching vibrations of the C=O
bonds of non-ionized carboxyl groups at 1700–1750 cm-1 are not present in 1. The ring wagging
vibration of the pyridyl group is also observed at 685 cm-1 for 1. The presence of a weak peak at
594 cm-1 may be assigned to the stretching vibration of the Cu–N bond [30] and that observed at
436 cm-1 is due to the stretch of the Cu–O bond [31].
To further characterize 1 its solid state structure that was already reported was elucidated
by single X-ray analysis [26]. Indeed, 1, isolated by us corresponds to the triclinic isomer
featured by a Cu(II) having a distorted square pyramidal CuNO4 chromophore with an almost
planar CuN1O1O2O3 unit, the value of the largest deviation from the mean plane being 0.21 Å
(see figures 2 and 3). The value of the trigonality parameter  is 0.052 [32]. The values of the
Cu–O and the Cu–N bond distances in the basal plane [2.022(4), 2.016(5), 1.988(4) and
1.921(5) Å)] for Cu1–O1, Cu1–O2, Cu1–O3 and Cu1–N1, respectively, are significantly shorter
5

than the apical interaction [Cu1–O4 (2.169(5) Å)]. The main source of distortion with respect to
the ideal square pyramid is due to the two fused five-membered chelate rings whose angles
subtended at the copper(II) ion by the tridentate L are 80.9(2) (N1–Cu1–O1) and 80.2(2)°
(N1Cu1–O2).
A relevant structural aspect concerns the environment of copper(II) ion because of the
weak axial Cu1O6a interaction [Cu…O6a: 3.175(4) Å; symmetry code: (a) = 1,0,0]. This
feature allows us to consider the surrounding of the copper center as an elongated octahedron.
This interaction leads to a supramolecular chain which runs along the crystallographic a axis.
3.2. Copper-catalyzed azide-alkyne cycloaddition
The catalytic performance of 1 was examined in the cycloaddition between phenylacetylene and
benzyl azide, which was chosen as a model reaction in order to optimize the catalytic conditions
(table 2). For this purpose, various solvents were screened pointing to water as a suitable solvent
for such a cycloaddition reaction. The reaction gave poor to moderate yields in hexane,
acetonitrile, ethanol and even in an ethanol/water mixture employed as solvents with 10 mol% of
1 (see entries 1-4, table 2). When using 5-15 mol% of precatalyst 1 in water as solvent, excellent
yields of the corresponding 1,2,3-triazole were obtained working at room temperature (entries
5-7, table 2). Even a further decrease of the precatalyst loading to 3 mol% led to a good yield
(entry 8, table 2). In light of these results, the use of 5 mol% of 1 in water at room temperature
appears to be suitable catalytic conditions for complex 1-mediated azide-alkyne cycloaddition
reactions.
After optimizing the conditions of the complex 1-mediated phenylacetylene-benzyl azide
cycloaddition, the catalytic scope of this complex was expanded to the cycloaddition of various
azide and alkyne derivatives (table 3). A variety of alkynes was reacted with benzyl azide using
5 mol% of 1 in water at room temperature (entries 1-6, table 3). The substrates containing
electron-withdrawing groups are less reactive than those containing electron-neutral and
electron-donating groups (entries 3 and 6, table 3); most of the reactions were completed within
24 h affording high yields of the corresponding 1,2,3-triazoles. In addition, a variety of azides
was reacted with phenyl acetylene resulting in formation of the corresponding 1,2,3-triazoles in
high yields (entries 7-9, table 3). The corresponding 1,2,3-triazoles were obtained in excellent
yields in all catalytic experiments and most importantly, the final products did not require further
6

purification by conventional methods. The products were fully characterized by their melting
point and also by 1H NMR, 13C NMR spectroscopy and mass spectrometry (Supporting
Information).
It appears that the process by which the catalytic active copper(I) species are generated to
catalyze azide-alkyne cycloaddition in water for such a long reaction time of 24 h occurs via
alkyne homocoupling. In fact, the presence of a reducing agent such as ascorbic acid or
hydrazine decreases the cycloaddition reaction time between benzyl azide and phenylacetylene,
being achieved in 45-50 min with very high yields of the 1,4-disubstituted 1,2,3-triazole
(entries 1 and 2, table 4). The corresponding 1,4-disubstituted-1,2,3-triazole was obtained in high
yield after 10 min using ascorbic acid as reducing agent under ultrasound irradiation conditions
(entry 3, table 4). However, under the same ultrasound conditions, clicking both azide and alkyne
substrates in the presence of 1 without reductant failed (entry 4, table 4).
By analogy with earlier results reported by Kuang [13, 33], the plausible mechanistic
pathways for synthesis of 1,4-disubstituted 1,2,3-triazoles in the presence of 1 is shown in
scheme 2. In the first step, the catalytic copper(I) species emerges via reducing 1 by terminal
alkyne via oxidative alkyne homocoupling reaction. Then, the catalytically active copper(I)
species formed in situ coordinates to the terminal alkyne to form the acetylide-copper
intermediate. In the second step, the copper-acetylide reacts with the azide derivative and a six-
membered copper-metallated triazolide results through rearrangement of the intermediate.
Finally, the intermediate copper triazoloid captures one proton to afford the final 1,2,3-triazole
product (scheme 2).
7

O
N
O
N
N
+
2+
R
1/2 R
O
Cu
+
OH
R
+
O
Cu
O
O
O
Cu
L
L
L
L
OH2
H2O
L= H2O
N
R
N
+
N
N
O
Cu
OH
+
R
L
H´
L
R
R
N
N
N
OH
N
OH
R
Cu
N
+
Cu
OH
R
L
OH
L
R'
OH
R'
N
N
N3
Cu
N
N
OH
N
R
+
OH
OH
Rearra
Cu
R
ngement
L
N
N
R'
N
Scheme 2. The proposed mechanism for the formation of 1,2,3-triazole mediated by 1.
To show the utility and potential of the 1-mediated azide-alkyne cycloaddition, we compared its
catalytic reactivity versus other copper(II) complexes (table 5). It is clear that the presence of a
reducing agent and the performance of the cycloaddition reaction at high-temperature and under
inert atmosphere are prerequisites for some catalytic systems to be operating. In contrast,
1-mediated azide-alkyne cycloaddition reaction occurs in an effective manner, working in air and
at room temperature in water, followed by an easy work-up protocol for the final separation of
1,2,3-triazole product.
8

4. Conclusion
Copper(II)-dipicolinate complex (1) was readily prepared in high yield via oxidation of copper(I)
iodide and the dipicolinic acid in water and acetonitrile as solvents in the presence of glycine.
The copper(II) environment is built by a nitrogen and two carboxylate-oxygens from a tridentate
dipicolinate ligand plus two water molecules. The complex mediates azide-alkyne cycloaddition
in effective and regioselective manners, leading to formation of a variety of 1,4-disubstituted-
1,2,3-triazoles. The present catalytic protocol is environmentally-benign because it is conducted
in water as solvent and it proceeds either in the presence or absence of reducing agents at room
temperature.
Supplementary material
Supplementary material associated with this article, including NMR spectroscopic and high
resolution mass spectrometry data and spectra, X-ray crystallographic data that confirm the
structure of 1, is included.
Acknowledgements
We are grateful to the Spanish Ministerio Español de Ciencia e Innovación (Project CTQ2016-
75068P), the Generalitat Valenciana (PROMETEO/2014/070), the Université Cadi Ayyad
(UCAM) the Centre National de la Recherche Scientifique (CNRS) and the Brest University.
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11

Table 1. Selected bond lengths (Å) and angles (°) of 1.
Cu1-N1
1.921(5)
2.022(4)
2.016(5)
1.988(4)
2.169(5)
96.1(2)
160.7(2)
94.0(2)
97.0(2)
98.8(2)
93.0(2)
80.9(2)
80.2(2)
157.6(2)
109.4(2)
Cu1-O1
Cu1-O2
Cu1-O3
Cu1-O4
O1-Cu1-O4
O2-Cu1-O1
O2-Cu1-O4
O3-Cu1-O1
O3-Cu1-O2
O3-Cu1-O4
N1-Cu1-O1
N1-Cu1-O2
N1-Cu1-O3
N1-Cu1-O4
12

Table 2. Optimization of the catalytic conditions for 1-mediated benzyl azide-
phenylacetylene cycloaddition reaction.
N
N
N
Ph
1
Complex
Ph
N
N
Ph
+
N
H2O / r.t.
Ph
1,4-isomer
Amount of catalyst
(mol%)
Entry
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
10
10
10
10
15
10
5
Hexane
Acetonitrile
Ethanol
Ethanol/Water
Water
48
55
60
70
97
95
90
70
Water
Water
3
Water
aReaction conditions: 0.313 mmol phenylacetylene, 0.376 mmol benzyl
azide, 24 h, 2 mL of solvent and r.t. bIsolated yields.
13

Table 3. Cycloaddition of azides with terminal alkynes in the presence of 1.
N
R'
N
N
1
Complex (5 mol%)
N
N
R
+
N
R'
H2O / r.t. / 24h
R
4
2
3
1,4-disubstitued 1,2,3-triazole
Entry
Alkyne
Azide
Products
Yield (%)
N3
1
4a
4b
90
N3
2
3
4
5
89
76
88
89
F
N3
4c
4d
4e
4f
N3
O
O
O
N3
N3
O
O
6
7
8
9
70
89
82
91
4g
N
N3
N3
F
4h
N3
O
4i
aReaction conditions: 0.313 mmol alkyne, 0.376 mmol azide, 24 h, 2 mL water and r.t.
bIsolated yields.
14

Table 4. Effect of the method for the syntheses of 1,4-disubstituted-1,2,3-triazole catalyzed by 1.
N
N
N
Ph
1
Complex
Ph
N
N
Ph
+
N
H2O / r.t.
Ph
1,4-isomer
Entry Additives
Time
Stirring method
Magnetic stirring
Magnetic stirring
Ultrasonic
Yield (%)
1
2
3
4
Ascorbic acid
Hydrazine
Ascorbic acid
-
50 min
45 min
10 min
30 min
96
95
85
Ultrasonic
Traces
Table 5. A comparison of 1 with previously reported precatalysts in the cycloaddition of benzyl
azide and phenylacetylene.
N
N
N
Ph
CuAAC
Ph
N
N
Ph
+
N
solvent
Ph
1,4-isomer
Time Yield
Entry Catalyst
Additives
Conditions
Ref.
(h)
20
4
(%)
1
2
3
Cu(NO3)2·3H2O
-
-
-
H2O/r.t.
13
[34]
[35]
[36]
[(C2H5)4N]4[V8Cu2O24]
Cu(II)-(C186 tren)a
H2O/70 °C
n-octane/r.t.
88
24
84
Sodium-
ascorbate
4
Cu(II)-(MBHTM)b
DMSO:H2O/r.t.
MeOH/N2/r.t.
4
94
99
[37]
Sodium-
ascorbate
5
6
Cu(II)-(BPPA)c
Cu(II)-(Phox)d
16
[38]
[39]
-
-
H2O/70 °C
H2O/r.t.
12
24
95
90
This
work
7
Complex 1
Sodium-
ascorbate
H2O/r.t.
1
96
aC186 tren: Tris(2-dioctadecylaminoethyl)amine). bMBHTM: (1-(4-Methoxybenzyl)-1-H-1,2,3-
triazol-4-yl)methanol. cBPPA: Bipyridinepyrazoleamine. dPhox: 2-(2′-hydroxyphenyl)-2-oxazoline
15

(a)
(b)
Cu-O
Cu-N
3500
3000
2500
2000
1500
1000
500
Wavenumberes (cm-1)
Figure 1. FT-IR spectra of (a) dipicolinic acid and (b) 1.
Figure 2. Perspective view of the structure of 1. The hydrogens have been omitted for clarity
[26].
16

a
Figure 3. View of the supramolecular chain of 1 along the [100] direction.
Graphical abstract
1
precatalyst
=
R'
N
N
N
+
N
R'
R
N
H2O / r.t.
N
Alkyne
Azide
R
Only 1,4-disubtitued 1,2,3-triazol
9 examples
yield: 70-91%
17