Hyperbranched polyethylenimine-supported copper(II) ions as a macroliganted homogenous catalyst for strict click reactions of azides and alkynes in water

Article abstract of DOI:10.1016/j.jorganchem.2019.120881

Loading hyperbranched polyethylenimine (PEI) with copper(II) ions leads to the formation of a new water-soluble metallodendritic polymer Cu(II)-PEI that has been found to effectively catalyze the clickable azide-alkyne [3 + 2] cycloaddition reactions in w

Full text of DOI:10.1016/j.jorganchem.2019.120881

Journal Pre-proof
Hyperbranched polyethylenimine-supported copper(II) ions as a macroliganted
homogenous catalyst for strict click reactions of azides and alkynes in water
Hicham Ben El Ayouchia, Hamid ElMouli, Lahoucine Bahsis, Hafid Anane, Rachid
Laamari, Carlos J. Gómez-García, Miguel Julve, Salah-Eddine Stiriba
PII:
S0022-328X(19)30324-9
DOI:
https://doi.org/10.1016/j.jorganchem.2019.120881
JOM 120881
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 12 June 2019
Revised Date: 26 July 2019
Accepted Date: 29 July 2019
Please cite this article as: H. Ben El Ayouchia, H. ElMouli, L. Bahsis, H. Anane, R. Laamari, C.J.
Gómez-García, M. Julve, S.-E. Stiriba, Hyperbranched polyethylenimine-supported copper(II) ions as a
macroliganted homogenous catalyst for strict click reactions of azides and alkynes in water, Journal of
Organometallic Chemistry (2019), doi: https://doi.org/10.1016/j.jorganchem.2019.120881.
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To be submitted to J. Organomet. Chem. (Second Revised Version)
Hyperbranched polyethylenimine-supported copper(II) ions as a
macroliganted homogenous catalyst for strict click reactions of azides
and alkynes in water
Hicham Ben El Ayouchiaa,*, Hamid ElMoulia, Lahoucine Bahsisa,*,Hafid Ananea,
Rachid Laamaria, Carlos J. Gómez-Garcíab, Miguel Julveb, and Salah-Eddine Stiribaa,b,*
aLaboratoire de Chimie Analytique et Moléculaire, - LCAM, Faculté Polydisciplinaire de Safi, Université
Cadi Ayyad, Safi 46030, Morocco.
bInstituto de Ciencia Molecular (ICMol), Universidad de Valencia, C/ Catedrático José Beltrán 2, 46980
Paterna, Valencia, Spain.
Abstract
Loading hyperbranched polyethylenimine (PEI) with copper(II) ions leads to the
formation of a new water-soluble metallodendritic polymer Cu(II)-PEI that has been
found to effectively catalyze the clickable azide-alkyne [3+2] cycloaddition reactions in
water under ambient conditions, in the lack of any external reducing agent. A positive
dendritic effect on the catalyst activity was observed in the click of 1,2,3-triazole by
lowering the reduction potential of copper(II) into the in-situ generation of the
catalytically active species copper(I). The reaction proceeds straightforwardly to afford
the corresponding 1,4-disubstituted-1,2,3-triazole derivatives in a regioselective
manner. The precatalystCu(II)-PEI has been easily recovered and reused for up to ten-
sequential applications with a decrease in its catalytic activity.
Keywords: Hyperbranched polyethylenimine; CuAAC; homogenous catalysis;
copper(I)-acetylide; 1,2,3-triazoles; DFT
*Corresponding authors: Tel./fax: +34963544445/+34963543273.
E-mail adress: salah.stiriba@uv.es (S.-E. Stiriba), belayou@gmail.com (H. Ben El Ayouchia),
bahsis.lahoucine@gmail.com (L. Bahsis)
1

1. Introduction
Alternative reaction media and procedures that use the immobilization of homogenous
catalysts to facilitate the catalysts separation play very important roles in green
chemistry by offering synthetic strategies with a low environmental cost. Indeed, efforts
are being made to apply environmentally benign solvents such as water, fluorinated,
ionic liquids and supercritical fluids as reaction media instead of toxic and/or hazardous
organic solvents together with inexpensive reagents and reusable catalytic systems
under very mild conditions, to set-up efficient greener synthesis of organic
compounds[1].
The Huisgen azide-alkyne cycloaddition reaction catalyzed by copper(I) (CuAAC) is
a relatively well-established strategy within the context of “click chemistry” which is
used for the formation of 1,4-disubstituted-1,2,3-triazoles and that has found broad
applicability in chemistry and biology. The 1,2,3-triazole unit, other than finding a large
use in molecular and polymer functionalization, has been applied to robust, chemically
orthogonal ligations for the study of complex biological systems[2-5]. The use of
copper(I) as a catalyst in CuAAC reactions, either as copper(I) or copper(II) salts
generated in situ by the reduction of Cu(II) with sodium ascorbate, is at the root of its
immense success as a fast kinetically and regioselective clickable process. However, the
direct employment of copper(I) presents many problems under aerobic conditions due to
its thermodynamic instability because of its oxidation into copper(II)[6]. In addition, the
copper ions are toxic and hazardous to the environment and human health[7,8], in
particular,copper(I) that passes through the biological membrane of living organisms,
being favored by the coordination environment of most of the biological cells[9, 10].
2

Consequently, special attention has recently been paid to metal-free strategies for the
click reaction of azides and alkynes [11, 12] by using stretched cycloalkynes[13] or by
adding electron-withdrawing substituents at the α position of the triple bond. Another
approach makes use of the substituted dibenzocyclooctyne[14].However, these
strategies are limited up to now to certain applications and these reactions are not
expected to replace CuAAC on a large scale, at least in the near future. In order to
overcome the presence of copper ions in both the final products as well as in the
reaction media, stable solid supports for copper catalysts, including copper(I/II)-
immobilized on silica[15], carbon[16,17], zeolite[18], alumina[19], biopolymers such
asCellulose[20], Chitosan[21], Alginate[22], and the chelation of copper to
dimethylaminomethyl-grafted cross-linked polystyrene (Amberlyst A-21 resin)[23-25]
have been developed as recoverable and reusable heterogeneous catalytic systems, with
improved catalytic activity in the lack of any external reducing agent. Other easy-to-
recover and to-reuse copper(I)-metallodendrimers have been scarcely explored as
polymeric catalysts in CuAAC under homogenous and heterogeneous fashions (see
Scheme 1), including the homogenous water-soluble copper-loaded poly(amidoamine)
(PAMAM) dendrimers, which proved to efficient in a model CuAAC reaction between
azido propanol and propargyl alcohol in water, as well as the heterogeneous copper-
stabilized cross-linked branched polyethylenimine employed for the click of polymeric
compounds[26].
3

Scheme 1.CuAAC using dendritic polymers as supports for the copper ion catalyst.
In most of the CuAAC reactions, a mixture of water and water-miscible organic
solvents has been used as solvent system. Water is the ideal solvent for greener
chemical organic processes because it is eco-friendly, non-toxic, cheap and abundant.
From this point of view, the performance of CuAAC reactions in water using a water-
soluble copper-loaded polymer without any organic solvent and reducing agent are
meaningful and valuable. We herein report on the employment of polyethylenimine
(PEI), a well-known biocompatible hyperbranched polyamine with high affinity and
selectivity for copper ions, to stabilize copper(II) sulfate and on the subsequent use of
the copper(II)-polyethylenimine complex [Cu(II)-PEI] under homogenous fashion in
clicking a series of azide and alkynes in water as reaction medium at room temperature
in absence of any external reducing agent. 1,4-Disubstituted-1,2,3-triazoles were
obtained regioselectively in excellent yields by simple precipitation in water. The
Cu(II)-PEI complex was reused for up to ten cycles without any loss of its activity and
selectivity.
4

2. Results and discussion
The Cu(II)-PEI macroligatedcomplex was prepared by a simple complexation
reaction at room temperature of hyperbranchedpolyethylenimine (PEI10K; Mn = 1 x 104
g mol-1, Mw/Mn = 2.5, NH2:NH:N = 33:40:27) and copper(II) sulfatepentahydrate in
DMF as solvent (Fig. 1). The complex was purified by dialysis against methanol to
remove any excess of CuSO4·5H2O affording a waxy-blue solid (see Scheme 2). The
UV-visible absorption spectra of the CuSO4·5H2O salt and the Cu(II)-PEI complex
dissolved in water were recorded in the wavelength range 200-800 nm. PEI is a
hyperbranched organic polymer that has no absorption over this range (Fig. 1a) whereas
the CuSO4·5H2O salt displays a typical absorption peak at 800 nm corresponding to d-d
transitions. Upon the coordination of the copper(II) ions to the colorless hyperbranched
PEI in solution, the mixture rapidly becomes deep blue, and the absorption spectrum
exhibits two absorption peaks at 275 and 610 nm (Fig. 1a).
Scheme 2. Preparative route for the metallodendritic polymer Cu(II)-PEI.
The hydrophilic and biocompatible PEI serves as a chelating polyamine for the
copper(II) ions. The occurrence of these absorption bands is due to the formation of the
Cu(II)-PEI complex (possibility 1-3, scheme 2). Both CuSO4·5H2O and Cu(II)-PEI
display two absorption bands in the region 200-800 nm. In the UV region, the
absorption bands below 280 nm are attributed to intra-ligand transitions while in the
5

visible region, the absorption band at 610 nm for Cu(II)-PEI and that at 800 nm for
CuSO4·5H2O are due to d-d transitions. In the spectrum of the Cu(II)-PEI complex (Fig.
1a), the absorption band at 800 nm found for CuSO4·5H2O undergoes a hypsochromic
shift to smaller wavelengths by 190 nm, this shift clearly indicating the complexation of
copper(II) to the PEI backbone. In order to quantify the amount of copper(II) ions
coordinated to the PEI backbone, we carried out a UV-visible spectroscopic study of the
absorption of the Cu(II) ions before and after complexation with PEI (λmax = 610 nm),
by varying the amount of copper (Fig. 1b and Fig. S1 in Supplemental Data). Increasing
amounts of CuSO4·5H2O were added to an aqueous solution containing a fixed amount
of PEI, and the absorbance of the resulting solution was recorded at the absorption band
of 610 nm. The absorption monitoring of this band shows that the loaded copper(II) ions
per PEI is about 2.62 mmol (0.65 g).
Aiming at understanding the interactions between the copper(II) and PEI, FT-IR
spectra of PEI and Cu(II)-PEI were recorded. The spectrum of PEI reveals the typical
frequencies of polyamines, such as the features at 3362 cm-1 [stretching vibration ν(N-
H)], 2948 and 2841 cm-1 [stretching vibrations ν(CH2) and ν(C-H)], 1569.7
[deformation vibration ν(N-H)], and 1473.5 cm-1 [deformation vibration ν(CH2)] and
finally the peaks at 1303 and 1472 cm-1 corresponding to the stretching vibration
ν(C−Ν)[27].The FT-IR spectrum of Cu(II)-PEI shows a new absorption peak around
619 cm-1 which corresponds to the Cu-N bond. In addition, a shift of the ν(N-H) signals
to 3447 cm-1, ν(NH2) (deformation vibration) to 1735 cm-1, ν(CH2) (deformation
vibration) to 1637 cm-1 and ν(C-N) (stretching vibration) to 1398 cm-1 also occur. These
shifts support the coordination of the copper(II) ions to the PEI backbone[28],
confirming the formation of the Cu(II)- PEI species (Fig. S2 in Supplemental Data).
6

Fig. 1. a) UV-Visible spectra of the CuSO4·5H2O salt and the Cu(II)-PEI complex in water. b) Evolution
of the absorbance at 610 nm as a function of the amount of copper(II) loaded by PEI.
The coordination mode of copper(II) to the nitrogen-containing polyethylenimine
backbone has been addressed by Electronic Paramagnetic Resonance (EPR). Variable-
temperature Q-band EPR study shows a quasi-isotropic signal with a line width of 22 G
at ca. 1.15 T (g = 2.120) in the temperature range 300-10 K. Below 10 K, the EPR
signal shows a slight broadening due to the increase of the anisotropy of the signal (Fig.
2). This EPR feature resembles those observed in other copper(II)-amine complexes
with a small anisotropy of the g factor. The lack of the expected hyperfine coupling in
these complexes is attributed to the slight anisotropy of the g factor and to the presence
of Cu(II)-Cu(II) interactions in the solid state[29]. This EPR signal confirms that the
7

copper(II) ions are bound to the amine groups of the hyperbranched PEI in a regular
coordination environment, adopting the surrounding indicated by the possibility 3 in
Scheme 1.
Fig. 2. Normalized Q-band EPR spectra of the Cu(II)-PEI complex at different temperatures.
The redox properties of copper(II) ions coordinated to the hyperbranched polymer
PEI backbone were studied by cyclic voltammetry in order to evaluate its potential
reduction and then tendency to form the catalytic active copper(I) species. Cyclic
voltammograms of CuSO4·5H2O and Cu(II)-PEI are shown in Fig. 3. The cathodic (Epc)
and anodic (Epa) peak potentials of copper(II) sulfate are -405 mV and 276 mV
respectively, with a large peak-to-peak separation (∆Ep) of 705 mV. The ratio of
cathodic to anodic peak current (ipc/ipa) is 1, indicating a quasi-reversible redox process
[30]. The formal potential (E1/2) which is taken as the average value of Epc and Epa is -
0.052 V. For the Cu(II)-PEI complex, a positive cathodic shift to Epc = 122 mV is
clearly observed with a better reversible redox (E1/2 = 0.077V) together with a decrease
in ∆Ep of 530 mV with respect to the parent copper(II) sulfate, which indicates that a
charge transfer from the nitrogen-containing polymer to the copper(II) ions is easier in
the Cu-PEI complex than in the precursor salt (vide infra), facilitating its reduction to
copper(I) ions. These results are in good agreement with those previouslyreported
8

results, where the Cu(II)/Cu(I) redox process was observed for copper(II) complexes
containing polydentate nitrogen ligands[31].
CuSO .5H2O
4
Epc
Cu(II)-PEI
100
0
-100
-200
-300
-800
-600
-400
-200
0
200
400
600
Potential (mV)
Fig. 3.Voltammograms of the CuSO4·5H2O salt and the Cu(II)-PEI complex.
Catalytic activity and reusability of Cu(II)-PEI in CuAAC
Optimization of the catalyst loading and reaction conditions for the [3+2]
cycloaddition process using phenylacetylene (1a) and benzyl azide (2a) were performed
in water as a benign reaction solvent. The results were very encouraging because the
reaction was completed after 24 hours at room temperature by simple precipitation of
the desired 1,2,3-triazole product (3a), which was obtained in a quantitative yield. The
progress of the reaction can be followed visually because of the cycloadduct precipitates
during the reaction in the aqueous medium (Fig. 4).
9

Fig. 4. Pictures of the resulting products before and after completion of the reaction by using the
Cu(II)-PEI complex.
Table 1. Catalyst loading and conditions screening for the click reaction of
phenylacetylene and benzyl azide.a
Entry
Cu-PEI (mol%)
Time (h)
Yield (%)b
1
2
3
10
5
1
24
24
48
99
98
95
aReaction conditions: azide (0.751 mmol), alkyne derivative (0.622 mmol), Cu(II)-PEI and 5 mL of
water.bIsolated yield.
It deserves to be noted that no external reducing agent was needed to perform the
copper(I)-catalyzed cycloaddition reaction between azides and alkynes, most likely
because the catalytically active copper(I) species was generated in situ by the reduction
of copper(II) into copper(I) by the terminal alkyne under the known Glaser
reaction;[32]a process which is facilitated by the presence of amine groups that lead to a
lowering of the redox potential of copper(II) ions. [33]No difference in the yield and
reaction times were observed when the amount of the catalyst was reduced from 10 to
10

5mol %. However, the reaction time was prolonged (48 h) when 1mol % of the catalyst
was used (Table 1).
The scope of Cu(II)-PEI in [3+2] cycloaddition reactions in water was explored, once
the optimal reaction conditions for the cycloaddition of benzyl azide and
phenylacetylene were established. Several [3+2] cycloaddition reactions of para-
substituted benzyl azide and phenyl azide derivatives by withdrawing/releasing groups
with different terminal phenylalkynes were carried out. The electron
withdrawing/releasing substituent groups do not have any particular effect, as most of
the reactions were completed within 24 h. A new triazole library has been created
(Table 2) and in all the cases, excellent yields of one regioisomer, namely 1,4-
disubstituted-1,2,3-triazole type, were obtained in good turnover numbers ranging from
16 and 19. All the synthesized triazole derivatives have been characterized by NMR
spectroscopy and HRMS analysis (see Supplemental Data).
On the basis of our best knowledge of previous reports[34-41],a stepwise mechanism
of cycloaddition is outlined in Fig. 5. The electron density of the alkyne in the proposed
mechanism is reduced by the copper(I) ion forming the dinuclear copper-acetylide B,
enabling an easy nucleophilic attack by the organoazide, resulting in the corresponding
complex C. The next step is a nucleophilic attack at N3 of the organoazide by the
acetylide carbon C4 forming the first covalent C–N bond and then producing the
intermediate D. The ring contraction of D leads to the formation of the triazolyl-copper
(E). The last step corresponds to a fast protonation of the copper triazolide, releasing the
final 1,2,3-triazole product as 1,4-regioisomer.
11

Table 2. Synthesis of the 1,2,3-triazoles (3a-3v) by clicking azides with alkynes in the
presence of the Cu(II)-PEI precatalyst.a,b,c
aReaction conditions: Azide (0.751 mmol), alkyne derivative (0.622 mmol) and 5 mol% of the Cu(II)-
b
c
PEI complex were placed in a reaction tube and 5 mL of water was added. Isolated yield. TON =
Turnover number catalyst moles of substrate/moles of catalyst.
12

Fig. 5. The proposed mechanism for the formation of 1,4-disubstituted-1,2,3-triazoles catalyzed by
Cu(II)-PEI.
The reusability of the catalyst is an important point when thinking of its practical
application. In order to address this issue, the reaction for the synthesis of the product
(3a) was chosen as a model reaction to explore the reusability of the catalytic water-
soluble system Cu(II)-PEI. After completion of the cycloaddition reaction in water at
room temperature, the organic precipitate was recovered by simple filtration and then,
additional phenylacetylene and benzyl azide were added to the remaining water
containing Cu(II)-PEI for a further run. This process of filtration-refilling with organic
reactants was performed until six times without any significant loss of efficiency and
selectivity of the Cu(II)-PEI and it undergoes a gradual decrease from the sixth
recycling as shown in the catalytic histogram of Fig. 6.
Fig. 6. Influence of the recycling on the efficiency of the Cu(II)-PEI species.
3. Conclusions
In summary, the preparation, characterization and applicability of the copper(II)-
loaded hyperbranchedpolyethylenimine Cu(II)-PEI as a new efficient and selective
water-soluble homogeneous catalyst in the CuAAC are reported. By using water as a
benign solvent medium, 1,4-disubstituted-1,2,3-triazoles were obtained as water-
13

insoluble white precipitates in excellent yields and in a regioselective manner at room
temperature in absence of any reducing agent or specific separation method. The
recovery/reusability of the catalyst was performed until ten catalytic cycleswitha
decrease in itscatalytic activity. These features make this protocol a reliable alternative
for the green synthesis of 1,2,3-triazole-1,4-disubstituted compounds.
4. Experimental procedure
4.1. Materials and methods
Hyperbranchedpolyethylenimine (PEI10K; Mn = 1 x 104 g mol, Mw/Mn = 2.5,
NH2:NH:N = 33:40:27) and copper(II) sulfate pentahydrate were purchased from
Sigma-Aldrich. All other reagents were purchased from Sigma-Aldrich and Across and
they were used as received without further purification. Anhydrous MgSO4 was used for
drying organic extracts and all volatiles were removed under reduced pressure.
Benzoylated cellulose tubings (MWCO 1000) for dialysis were purchased from Sigma.
The reactions were performed in the open air. All reaction mixtures were monitored by
TLC using commercial glass backed thin layer chromatography (TLC) plates (Merck
Kieselgel 60 F254). The plates were observed under UV-light at 254 nm. NMR analyses
were carried out on a Brucker AC-400 MHz spectrometer (400 MHz for proton, 100
MHz for carbon) by using deuterated chloroform as solvent. The chemical shifts (δ) are
expressed in ppm. The high-resolution mass spectra (HRMS) were recorded in the EI
(70 eV) or FAB mode at the mass spectrometry service of the University of Valencia.
FT-IR spectra (400-4000 cm-1 range) were recorded on with a Nicolet 5700 FT-IR
spectrometer. Melting points were determined using a Stuart melting point apparatus
SMP3, employing the capillary tubes. EPR measurements were performed with a Q-
band (34 GHz) Bruker E-580 ELEXSYS spectrometer on a powder sample in the 4-300
K temperature range.
14

4.2. Procedure for synthesis of the benzyl azide derivatives
A given benzyl bromide derivative (5.85 mmol) and NaN3 (17.5 mmol) were
dissolved in 20 mL of DMF. The reaction mixture was stirred and protected from light
for 20 hours at room temperature. After filtration, water was added to the filtrate and the
product was extracted with dichloromethane three times. The organic phases were
combined and dried over anhydrous MgSO4 then filtered and solvents were evaporated
under vacuum, affording a liquid product.
Caution! Azide salts are potentially explosive and should be handled with care and in
small quantities.
4.3. Procedure for synthesis of the aryl azide derivative
The aniline derivative (13 mmol) was suspended in 80 mL hydrochloric acid (17 %)
at room temperature and then ethanol was added until a clear solution was obtained. The
solution was cooled to 0 °C and NaNO2 (19.5 mmol) was added in small amounts. After
stirring at 0 °C for 15-30 min. NaN3 (19.5 mmol) was slowly added and the mixture was
stirred for additional 2 h at room temperature. The reaction mixture was extracted with
diethyl ether (3 x 80 mL) and the combined organic fractions were washed with a
saturated NaHCO3 solution (3 x 50 mL) and with brine (50 mL). After drying over
MgSO4, the ether was removed under reduced pressure and the wanted azides were
obtained without further purification.
4.4. General procedure for the synthesis of Cu(II)-PEI complex
The polyethylenimine PEI (1 g, 0.02 mol of amine groups) was dissolved in 30 mL of
DMF and CuSO4·5H2O (0.005 mol, 1.2 g) was added and stirred for 30 min at room
temperature, after evaporation of the solvent under vacuum, the complex was washed
with hexane and diethyl ether and purified by dialysis (dialysis tubing,
15

benzoylatedcellulose MWCO 1000) in MeOH over two days to afford Cu(II)-PEI as a
waxy blue solid that was dried and then characterized by FT-IR on a NaCl film, UV-
Visible spectroscopy, electronic paramagnetic resonance (EPR) and cyclic voltammetry.
4.5. General procedure for Cu(II)-PEI–catalyzed [3+2] cycloaddition reaction of azide-
alkyne derivatives
Azide (0.751 mmol), alkyne derivative (0.622 mmol) and 5 mol% of the Cu(II)-PEI
complex were placed in a reaction tube and 5 mL of water was added. The reaction tube
was placed on a magnetic stirrer and the reaction mixture was stirred for 24 h at room
temperature. After completion of the reaction that can be visually monitored, due to the
precipitation of the triazolic product, the mixture was filtered off and the white solid
was dried. The recovered Cu(II)-PEI in the aqueous phase was reused at least ten times
by adding the starting azide and alkyne reagents.
Acknowledgments
This work was supported by Université Cadi Ayyad and the MinisterioEspañol de
Economia y Competitividad (Project CTQ2016-75068P).
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19

HIGHLIGHTS
- Copper-catalyzed azide-alkyne [3+2] cycloadditon reactions were efficiently achieved
by using hyperbranched polyethylenimine loaded by a copper(II) precursor.
- The click of 1,2,3-triazoles was performed in a regioselective manner under ambient
conditions in water in absence of any external reducing agent.
- The dendritic catalyst was recovered and reused with a decrease in its catalytic
activity, evidencing its sustainable nature.